Rip1 inhibitory compounds and methods for making and using the same

ABSTRACT

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/402,111, filed on May 2, 2019, which claims the benefit of theearlier filing date of U.S. Provisional Application No. 62/666,462,filed on May 3, 2018; the entirety of each of these prior applicationsis incorporated herein by reference.

FIELD

The present disclosure concerns compounds and methods of making andusing the compounds, such as for inhibiting receptor-interactingprotein-1 kinase (“RIP1”), and for treating diseases and/or conditionsrelated to RIP1.

BACKGROUND

Receptor-interacting protein-1 kinase (referred to herein as “RIP1”)belongs to the tyrosine kinase-like family and is a serine/threonineprotein kinase involved in innate immune signaling. RIP1 plays a centralrole in regulating cell signaling and its role in programmed cell deathhas been linked to various inflammatory diseases, such as inflammatorybowel disease, psoriasis, and other diseases and/or conditionsassociated with inflammation and/or necroptotic cell death.

SUMMARY

Disclosed herein are compound embodiments having a Formula I

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that compounds within the scope ofFormula I also include stereoisomers, N-oxides, tautomers, hydrates,solvates, isotopes, and/or prodrugs thereof.

With reference to Formula I, ring B is 5-membered or 6-memberedheteroaryl; L is a heteroatom or R^(a), provided that R^(a) is not H orD; Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl,or C₃₋₆cycloalkyl); or

R¹ is a halogen, —C≡CH, or a -linker-R⁶ group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R^(b), —C(R^(f))₃,or —C(R^(f))═C(R^(f))₂; R² and R³ independently are R^(a); R⁴ and R⁵independently are R^(e); R^(a) is independently for each occurrence H,D, C₁₋₁₀aliphatic, C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, orC₃₋₆heterocyclic; R^(b) is independently for each occurrence —OH, —SH,—OR^(c), —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or—C(O)NR^(d)R^(d); R^(c) is independently for each occurrence C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₆cycloalkyl (which can be substitutedwith 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can be substituted with1, 2 or 3 R^(e)); R^(d) is independently for each occurrence H;C₁₋₆alkyl (which can be substituted with 1, 2 or 3 R^(e));C₃₋₆cycloalkyl (which can be substituted with 1, 2 or 3 R^(e));C₃₋₆heterocyclic (which can be substituted with 1, 2 or 3 R^(e));C₅₋₁₀aryl (which can be substituted with 1, 2 or 3 R^(e));C₅₋₁₀heteroaryl (which can be substituted with 1, 2 or 3 R^(e)); or twoR^(d) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic (which can be substituted with one or more R^(e)), or aC₅₋₁₀heteroaryl (which can be substituted with one or more R^(e)); R^(e)is independently for each occurrence halogen, C₁₋₆alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₆haloalkyl C₃₋₆cycloalkyl, C₅₋₁₀heteroaryl, or —OR^(a);R^(f) is independently for each occurrence R^(a), R^(b), or R^(c), ortwo R^(f) groups together with the carbon atom bound thereto provide aC₃₋₆cycloalkyl group (which can be substituted with one or more R^(e)),or a C₃₋₁₀heterocyclic (which can be substituted with one or moreR^(e)); m is 1 to 4; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4, or 5.

Disclosed compounds may have a structure satisfying the formula below

In any or all of the above embodiments, ring B can have a structuresatisfying a formula

wherein at least one W is nitrogen, and each remaining W independentlyis selected from carbon, CH, oxygen, sulfur, nitrogen, or NH, withparticular ring B embodiments being a diazole, a triazole, anoxadiazole, an oxazole, or a pyridinyl. Suitable exemplary triazolesinclude any of the following:

Suitable exemplary diazole include any of the following:

Suitable exemplary oxadiazoles include any of the following:

Suitable exemplary oxazoles include any of the following:

Certain disclosed compounds comprise an R⁵ group that is an R^(e) group,wherein R^(e) is C₁-C₄aliphatic, or halogen, R² is R^(a) wherein R^(a)is C₁-C₄aliphatic, and R³ is R^(a), wherein R^(a) is hydrogen.

For certain disclosed embodiments, R¹ is a linker-R⁶ group wherein thelinker is R^(a) and R^(a) is a C₁, C₂, C₃, or C₄ aliphatic group. The C₂aliphatic group may be an alkyl, alkenyl, or alkynyl group. The R⁶ groupmay be R wherein R is —C(R^(f))₃, wherein one R^(f) is R^(e),particularly —OR^(a), wherein R^(a) is H; and each other R^(f)independently for each occurrence is R^(a), wherein R^(a) is C₁₋₄alkyl,particularly methyl. In particular embodiments, the C₂ group is analkyne. In any or all of the above embodiments, ring B can be selectedfrom

In some embodiments, R⁶ may be R^(b) wherein R^(b) is —C(O)OEt; or R^(b)may be —C(O)NR^(d)R^(d), wherein each R^(d) is independently for eachoccurrence H, C₅₋₁₀heteroaryl (which can be substituted with 1, 2 or 3R^(e)), C₁₋₆alkyl (which can be substituted with 1, 2 or 3 R^(e)), ortwo R^(d) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic (which can be substituted with one or more R^(e)), or aC₅₋₁₀heteroaryl (which can be substituted with one or more R^(e)). Moreparticularly, one R^(d) is H and the other R^(d) is aromatic, such as

Certain compounds can comprise an R⁶ group that is R^(b) wherein R^(b)is —OH; OR^(c), wherein R^(c) is C₁₋₁₀alkyl (which can be substitutedwith 1, 2 or 3 R^(c)), C₂₋₁₀alkenyl (which can be substituted with 1, 2or 3 R^(e)), C₂₋₁₀alkynyl (which can be substituted with 1, 2 or 3R^(e)), or C₅₋₁₀aromatic (which can be substituted with 1, 2 or 3R^(e)); or NR^(d)R^(d), wherein one R^(d) is H and the other R^(d) isC₅₋₁₀aromatic (which can be substituted with 1, 2 or 3 R^(e)). In someembodiments, R^(b) is OR^(c), wherein R^(c) is C₂alkyl substituted withpyridinyl. In some other embodiments, R^(b) may be —NR^(d)R^(d), whereinone R^(d) is H and the other R^(d) is pyridinyl.

The linker group of the linker-R⁶ group can be a C₁ group and thecorresponding R⁶ group is R^(b) wherein R^(b) is —NR^(d)R^(d), whereintwo R^(d) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic (which can be substituted with one or more R^(e)), or aC₅₋₁₀heteroaryl (which can be substituted with one or more R^(e)),particularly wherein two R^(d) groups together with the nitrogen boundthereto provide a C₃₋₉heterocyclic substituted with one R^(e). In suchembodiments, R^(e) may be C₅₋₁₀heteroaryl, such as pyridinyl. In otherembodiments, the two R^(d) groups together with the nitrogen to whichthey are bound may provide a C₅₋₁₀heteroaryl optionally may besubstituted with one or more R^(e). The C₅₋₁₀heteroaryl without R^(e)substituents can be

In some embodiments, R⁵ is R^(e), wherein R^(e) is halogen or methyl. Insome embodiments, the linker of the linker-R⁶ group is R^(a) whereinR^(a) is a C₁, C₂, C₃, or C₄ aliphatic group comprising an alkyl,alkenyl, or alkynyl group. In some such embodiments, the C₂ groupcomprises an alkyne and wherein R⁶ is R^(b) wherein R^(b) is —C(R^(f))₃,wherein one R^(f) is R^(e) and each other R^(f) independently for eachoccurrence is R^(a), wherein R^(a) is C₁₋₄alkyl. In particularembodiments, R^(e) is —OR^(a), wherein R^(a) is H. R^(a) is methyl insome such embodiments and ring B is

R¹ can be positioned on any suitable carbon atom(s) of phenyl ring A,such as at the 1, 2, 3, or 4 position, illustrated in Formula I.Exemplary R¹ groups are as follows:

Exemplary compound species are provided herein.

Also disclosed herein are pharmaceutical composition embodimentscomprising a compound (or compounds) according to any of the formulasand/or species disclosed herein (or a pharmaceutically acceptable salt,a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, anisotope, or a prodrug thereof), and at least one additional activeand/or non-active agent, such as an excipient, a therapeutic agent, anadjuvant, or combinations thereof.

Also disclosed herein are embodiments of a method for using disclosedcompounds. One such embodiment comprises contacting areceptor-interacting protein-1 (RIP1) kinase with a compound accordingto any of the formulas and/or species disclosed herein (or apharmaceutically acceptable salt, a stereoisomer, an N-oxide, atautomer, a hydrate, a solvate, an isotope, or a prodrug thereof), or apharmaceutical composition embodiment described herein. Contacting canoccur ex vivo or in vivo.

Also disclosed is a method for treating a disease in a subject,comprising administering to the subject (i) a therapeutically effectiveamount of the compound according to any of the formulas and/or speciesdisclosed herein (or a pharmaceutically acceptable salt, a stereoisomer,an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrugthereof); and/or (ii) a therapeutically effective amount of apharmaceutical composition embodiment described herein; wherein thesubject has, or is suspected of having or developing a disease involvinga receptor-interacting protein-1 (RIP1) kinase.

Method embodiments for making the compound embodiments disclosed hereinalso are described. In some embodiments, the method can comprisecoupling a starting material having a Formula A with an R-containingreagent, by combining the starting material and the R¹-containingreagent, wherein R¹ comprises a linker-R⁶ group, with a transition metalcatalyst, a base, and a solvent to form a functionalized product;deprotecting an amine group of the functionalized product to provide anamine compound; and forming an amide bond between the amine compound andan acid-containing coupling partner to provide an amide-containingcompound; wherein Formula A is

the functionalized product has a structure satisfying Formula B

and the acid-containing coupling partner has a structure satisfyingFormula C

and whereinX is a halogen or a triflate;PG is an amine protecting group;and each of ring B, L, R¹, R², R⁴, R⁵, m, n, and p are as recited forany one or more of the above compound embodiments.

The foregoing and other objects and features of the present disclosurewill become more apparent from the following detailed description.

DETAILED DESCRIPTION I. Overview of Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements. Allreferences, including patents and patent applications cited herein, areincorporated by reference.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is expressly recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

If an R group is depicted as “floating” on a ring system, as for examplewith R¹ in the group:

then, unless otherwise defined, a substituent R (e.g., R¹ above) canreside on any atom of the fused bicyclic ring system, excluding the atomcarrying the bond with the “

” symbol, so long as a stable structure is formed.

When a group R is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, y can be more than one, assuming each replaces acurrently depicted, implied, or expressly defined hydrogen on the ring;then, unless otherwise defined, two R's can reside on the same carbon. Asimple example is when R is a methyl group. The depicted structure canexist as a geminal dimethyl on a carbon of the depicted ring (an“annular” carbon). In another example, two R's on the same carbon,including that same carbon, can be included in a ring, thus creating aspirocyclic ring (a “spirocyclyl” group) structure.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted unless the context indicates otherwise or aparticular structural formula precludes substitution. In particularembodiments, a substituent may or may not be expressly defined assubstituted, but is still contemplated to be optionally substituted. Forexample, an “aliphatic” or a “cyclic” moiety may be unsubstituted orsubstituted, but an “unsubstituted aliphatic” or an “unsubstitutedcyclic” is not substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety can be, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₁₀aliphatic, heteroaliphatic, or cycloaliphatic, typically,C₁₋₆aliphatic, more typically C₁₋₆alkyl, where R⁶⁰ optionally may besubstituted; each R⁷⁰ is independently for each occurrence hydrogen orR⁶⁰; each R⁸⁰ is independently for each occurrence R⁷⁰ or alternatively,two R⁸⁰ groups, taken together with the nitrogen atom to which they arebonded, form a 3- to 7-membered heterocycloaliphatic, which optionallyincludes from 1 to 4 of the same or different additional heteroatomsselected from O, N and S, of which N optionally has R⁷⁰ substitution,such as H or C₁-C₃alkyl substitution; and each M⁺ is a counter ion witha net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as ⁺N(R⁶⁰)₄; a protonated amino acid ion, such as alysine ion, or an arginine ion; or an alkaline metal earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a subscript “0.5” means,for example, that one of the counter ions for such divalent alkali earthions can be an ionized form of a compound of the invention and the othera typical counter ion such as chloride, or two ionized compounds canserve as counter ions for such divalent alkali earth ions, or a doublyionized compound can serve as the counter ion for such divalent alkaliearth ions). As specific examples, —N(R⁸⁰)₂ includes —NH₂, —NH-alkyl,—NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon also can be replaced with, for example, ═O,═NR⁷⁰, ═N—OR⁷⁰, ═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined. In an independent embodiment, the substituentsare not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰,—PO₃ ²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In one embodiment, a group that is substituted has at least onesubstituent up to the number of substituents possible for a particularmoiety, such as 1 substituent, 2 substituents, 3 substituents, or 4substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

Any group or moiety defined herein can be connected to any other portionof a disclosed structure, such as a parent or core structure, as wouldbe understood by a person of ordinary skill in the art, such as byconsidering valence rules, comparison to exemplary species, and/orconsidering functionality, unless the connectivity of the group ormoiety to the other portion of the structure is expressly stated, or isimplied by context.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, or aromatic (including both aryl and heteroaryl).Exemplary acyl moieties include, but are not limited to, —C(O)H,—C(O)alkyl, —C(O)C₁-C₆alkyl, —C(O)C₁-C₆haloalkyl, —C(O)cycloalkyl,—C(O)alkenyl, —C(O)cycloalkenyl, —C(O)aryl, —C(O)heteroaryl, or—C(O)heterocyclyl. Specific examples include, —C(O)H, —C(O)Me, —C(O)Et,or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety.An aliphatic group or moiety can be acyclic, including alkyl, alkenyl,or alkynyl groups (as well as alkylene, alkenylene, or alkynylenegroups), cyclic versions thereof, such as cycloaliphatic groups ormoieties including cycloalkyl, cycloalkenyl or cycloalkynyl, and furtherincluding straight- and branched-chain arrangements, and all stereo andposition isomers as well. Unless expressly stated otherwise, analiphatic group contains from one to twenty-five carbon atoms (C₁₋₂₅);for example, from one to fifteen (C₁₋₁₅), from one to ten (C₁₋₁₀) fromone to six (C₁₋₆), or from one to four carbon atoms (C₁₋₄) for anacyclic aliphatic group or moiety, or from three to fifteen (C₃₋₁₅) fromthree to ten (C₃₋₁₀), from three to six (C₃₋₆), or from three to four(C₃₋₄) carbon atoms for a cycloaliphatic group or moiety. An aliphaticgroup may be substituted or unsubstituted, unless expressly referred toas an “unsubstituted aliphatic” or a “substituted aliphatic.” Analiphatic group can be substituted with one or more substituents (up totwo substituents for each methylene carbon in an aliphatic chain, or upto one substituent for each carbon of a —C═C— double bond in analiphatic chain, or up to one substituent for a carbon of a terminalmethine group).

“Lower aliphatic” refers to an aliphatic group containing from one toten carbon atoms (C₁₋₁₀), such as from one to six (C₁₋₆), or from one tofour (C₁₋₄) carbon atoms; or from three to ten (C₃₋₁₀), such as fromthree to six (C₃₋₆) carbon atoms for a lower cycloaliphatic group.

“Alkoxy” refers to the group —OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group.In certain examples R is a C₁₋₆ alkyl group or a C₃₋₆cycloalkyl group.Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃) are exemplary alkoxy groups. In asubstituted alkoxy, R is substituted alkyl or substituted cycloalkyl,examples of which in the presently disclosed compounds includehaloalkoxy groups, such as —OCF₂H.

“Alkoxyalkyl” refers to the group -alkyl-OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group;—CH₂CH₂—O—CH₂CH₃ is an exemplary alkoxyalkyl group.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to at least 25 (C₁₋₂₅) carbon atoms, more typically 1 to 10 (C₁₋₁₀)carbon atoms such as 1 to 6 (C₁₋₆) carbon atoms. An alkyl moiety may besubstituted or unsubstituted. This term includes, by way of example,linear and branched hydrocarbyl groups such as methyl (CH₃), ethyl(—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aromatic,including both aryl and heteroaryl, or heterocycloaliphatic, or two Rgroups together with the nitrogen attached thereto form a heterocyclicring. Examples of such heterocyclic rings include those wherein two Rgroups together with the nitrogen to which they are attached form a—(CH₂)₂₋₅— ring optionally interrupted by one or two heteroatom groups,such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(R)acyl, wherein R is hydrogen,heteroaliphatic, or aliphatic, such as alkyl, particularly C₁₋₆alkyl.

“Aromatic” refers to a cyclic, conjugated group or moiety of, unlessspecified otherwise, from 5 to 15 ring atoms having a single ring (e.g.,phenyl, pyridinyl, or pyrazolyl) or multiple condensed rings in which atleast one ring is aromatic (e.g., naphthyl, indolyl, orpyrazolopyridinyl), that is at least one ring, and optionally multiplecondensed rings, have a continuous, delocalized π-electron system.Typically, the number of out of plane π-electrons corresponds to theHückel rule (4n+2). The point of attachment to the parent structuretypically is through an aromatic portion of the condensed ring system.For example,

However, in certain examples, context or express disclosure may indicatethat the point of attachment is through a non-aromatic portion of thecondensed ring system. For example,

An aromatic group or moiety may comprise only carbon atoms in the ring,such as in an aryl group or moiety, or it may comprise one or more ringcarbon atoms and one or more ring heteroatoms comprising a lone pair ofelectrons (e.g. S, O, N, P, or Si), such as in a heteroaryl group ormoiety. Unless otherwise stated, an aromatic group may be substituted orunsubstituted.

“Aryl” refers to an aromatic carbocyclic group of, unless specifiedotherwise, from 6 to 15 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings in which at least one ring is aromatic(e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If anyaromatic ring portion contains a heteroatom, the group is heteroaryl andnot aryl. Aryl groups may be, for example, monocyclic, bicyclic,tricyclic or tetracyclic. Unless otherwise stated, an aryl group may besubstituted or unsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Carboxyl” refers to —CO₂H.

“Carboxamide” refers to —C(O)amino.

“Carboxyl ester” or “carboxy ester” refers to the group —C(O)OR, where Ris aliphatic, heteroaliphatic, or aromatic (including both aryl andheteroaryl).

“Carboxylate” refers to —C(O)O or salts thereof.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, the ring or at least one of the rings in the systemis aliphatic. Typically, the point of attachment to the parent structureis through an aliphatic portion of the multiple ring system.Cycloaliphatic includes saturated and unsaturated systems, includingcycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group maycontain from three to twenty-five carbon atoms; for example, from threeto fifteen, from three to ten, or from three to six carbon atoms. Unlessotherwise stated, a cycloaliphatic group may be substituted orunsubstituted. Exemplary cycloaliphatic groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, or cyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl moiety substituted with one or morehalogens. Exemplary haloalkyl moieties include —CH₂F, —CHF₂ and —CF₃.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom and at least one carbon atom, i.e., at least onecarbon atom from an aliphatic compound or group comprising at least twocarbon atoms, has been replaced with an atom having at least one lonepair of electrons, typically nitrogen, oxygen, phosphorus, silicon, orsulfur. Heteroaliphatic compounds or groups may be substituted orunsubstituted, branched or unbranched, chiral or achiral, and/or acyclicor cyclic, such as a heterocycloaliphatic group.

“Heteroaryl” refers to an aromatic group or moiety having, unlessspecified otherwise, from 5 to 15 ring atoms comprising at least onecarbon atom and at least one heteroatom, such as N, S, O, P, or Si. Aheteroaryl group or moiety may comprise a single ring (e.g., pyridinyl,pyrimidinyl or pyrazolyl) or multiple condensed rings (e.g., indolyl,benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moiety maybe, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unlessotherwise stated, a heteroaryl group or moiety may be substituted orunsubstituted.

“Heterocyclyl,” “heterocyclo” and “heterocycle” refer to both aromaticand non-aromatic ring systems, and more specifically refer to a stablethree- to fifteen-membered ring moiety comprising at least one carbonatom, and typically plural carbon atoms, and at least one, such as fromone to five, heteroatoms. The heteroatom(s) may be nitrogen, phosphorus,oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be amonocyclic moiety, or may comprise multiple rings, such as in a bicyclicor tricyclic ring system, provided that at least one of the ringscontains a heteroatom. Such a multiple ring moiety can include fused orbridged ring systems as well as spirocyclic systems; and any nitrogen,phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moietycan be optionally oxidized to various oxidation states. For convenience,nitrogens, particularly, but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.Thus, for a compound having, for example, a pyridinyl ring, thecorresponding pyridinyl-N-oxide is included as another compound of theinvention, unless expressly excluded or excluded by context. Inaddition, annular nitrogen atoms can be optionally quaternized.Heterocycle includes heteroaryl moieties, and heteroalicyclyl orheterocycloaliphatic moieties, which are heterocyclyl rings that arepartially or fully saturated. Examples of heterocyclyl groups include,but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic, such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; —O-aralkyl; or—OR′ is —O⁻M⁺, where M⁺ is a counter ion with a single positive charge.Each M⁺ may be an alkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonooxyalkyl refers tothe group -alkyl-phosphate, such as, for example, —CH₂OP(O)(OH)₂, or asalt thereof, such as —CH₂OP(O)(O—Na⁺)₂, and(((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of aphosphonooxyalkyl group, such as, for example, —CH₂OP(O)(O-tert-butyl)₂.

“Phosphonate” refers to the group —P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; or —O-aralkyl; or—OR′ is —O⁻M⁺, and M⁺ is a counter ion with a single positive charge.Each M⁺ is a positively charged counterion and may be, by way ofexample, an alkali metal ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth metal ion,such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonoalkylrefers to the group -alkyl-phosphonate, such as, for example,—CH₂P(O)(OH)₂, or —CH₂P(O)(O⁻Na⁺)₂, and ((dialkoxyphosphoryl)alkyl)refers to the dialkyl ester of a phosphonoalkyl group, such as, forexample, —CH₂P(O)(O-tert-butyl)₂.

“Patient” or “Subject” may refer generally to any living being, but moretypically refers to mammals and other animals, particularly humans. Thusdisclosed methods are applicable to both human therapy and veterinaryapplications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient, that is included in a composition comprisingthe active ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, anti-adherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, carriers or vehicles.Excipients may be starches and modified starches, cellulose andcellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is a component that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as Freund's complete adjuvant orFreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Remington: The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, Pa., 21^(st) Edition (2005),incorporated herein by reference, describes exemplary compositions andformulations suitable for pharmaceutical delivery of one or moretherapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like. “Pharmaceutically acceptable acidaddition salts” are a subset of “pharmaceutically acceptable salts” thatretain the biological effectiveness of the free bases while formed byacid partners. In particular, the disclosed compounds form salts with avariety of pharmaceutically acceptable acids, including, withoutlimitation, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, as well asorganic acids such as amino acids, formic acid, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,benzene sulfonic acid, isethionic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoicacid and the like. “Pharmaceutically acceptable base addition salts” area subset of “pharmaceutically acceptable salts” that are derived frominorganic bases such as sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Exemplary salts are the ammonium, potassium, sodium, calcium, andmagnesium salts. Salts derived from pharmaceutically acceptable organicbases include, but are not limited to, salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the compounds may be a formate, trifluoroactate,hydrochloride or sodium salt.

“Effective amount” with respect to a compound or pharmaceuticalcomposition refers to an amount of the compound or pharmaceuticalcomposition sufficient to achieve a particular desired result, such asto inhibit a protein or enzyme. In particular embodiments, an “effectiveamount” is an amount sufficient to inhibit RIP1; to elicit a desiredbiological or medical response in a tissue, system, subject or patient;to treat a specified disorder or disease; to ameliorate or eradicate oneor more of its symptoms; and/or to prevent the occurrence of the diseaseor disorder. The amount of a compound which constitutes an “effectiveamount” may vary depending on the compound, the desired result, thedisease state and its severity, the size, age, and gender of the patientto be treated and the like, as will be understood by a person ofordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, or a compound more biologically activethan the parent compound. In vivo transformation may occur, for example,by hydrolysis or enzymatic conversion. Common examples of prodrugmoieties include, but are not limited to, ester and amide forms of acompound having an active form bearing a carboxylic acid moiety.Examples of pharmaceutically acceptable esters of the compounds of thisinvention include, but are not limited to, esters of phosphate groupsand carboxylic acids, such as aliphatic esters, particularly alkylesters (for example C₁₋₆alkyl esters). Other prodrug moieties includephosphate esters, such as —CH₂—O—P(O)(OR′)₂ or a salt thereof, whereinR′ is H or C₁₋₆alkyl. Acceptable esters also include cycloalkyl estersand arylalkyl esters such as, but not limited to benzyl. Examples ofpharmaceutically acceptable amides of the compounds of this inventioninclude, but are not limited to, primary amides, and secondary andtertiary alkyl amides (for example with between about one and about sixcarbons). Amides and esters of disclosed exemplary embodiments ofcompounds according to the present invention can be prepared accordingto conventional methods. A thorough discussion of prodrugs is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of a solute. The solvent can be an organicsolvent, an inorganic solvent, or a mixture of both. Exemplary solventsinclude, but are not limited to, alcohols, such as methanol, ethanol,propanol; amides such as N,N-dialiphatic amides, such asN,N-dimethylformamide; tetrahydrofuran; alkylsulfoxides, such asdimethylsulfoxide; water; and combinations thereof. The compoundsdescribed herein can exist in un-solvated as well as solvated forms whencombined with solvents, pharmaceutically acceptable or not, such aswater, ethanol, and the like. Solvated forms of the presently disclosedcompounds are within the scope of the embodiments disclosed herein.

“Sulfonamide” refers to the group or moiety —SO₂amino, or —N(R)sulfonyl,where R is H, aliphatic, heteroaliphatic, or aromatic (including botharyl and heteroaryl).

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-heteroaliphatic,—S-aromatic, (including both-S-aryl and —S-heteroaryl).

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)heteroaliphatic, or —S(O)aromatic (including both —S(O)aryl and—S(O)heteroaryl).

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic,—SO₂heteroaliphatic, —SO₂aromatic (including both —SO₂aryl and—SO₂heteroaryl).

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, particularly a humanhaving the disease or condition of interest, and includes by way ofexample, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingdiminution of a symptom or regression of the disease or condition or asymptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, a person of ordinary skill in the art will appreciatethat the disclosed compounds encompass any tautomeric, conformationalisomeric, optical isomeric, and/or geometric isomeric forms of thecompounds described herein, as well as mixtures of these variousdifferent isomeric forms. Mixtures of different isomeric forms,including mixtures of enantiomers and/or stereoisomers, can be separatedto provide each separate enantiomers and/or stereoisomer usingtechniques known to those of ordinary skill in the art, particularlywith the benefit of the present disclosure. In cases of limitedrotation, e.g. around the amide bond or between two directly attachedrings such as pyridinyl rings, biphenyl groups, and the like,atropisomers are also possible and are also specifically included in thecompounds of the invention.

In any embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be replaced by adeuterium or a tritium. Thus, a recitation of alkyl includes deuteratedalkyl, where from one to the maximum number of hydrogens present may bereplaced by deuterium. For example, ethyl refers to both C₂H₅ or C₂H₅where from 1 to 5 hydrogens are replaced by deuterium, such as inC₂D_(x)H_(5-x).

II. RIP1-Active Compounds and Pharmaceutical Compositions ComprisingRIP1-Active Compounds

A. Compounds

Disclosed herein are compounds and pharmaceutical compositionscomprising such compounds that are useful for inhibiting RIP1 and/or fortreating diseases and/or conditions associated with RIP1. In someembodiments, the compounds are selective kinase inhibitors. For example,exemplary compounds are able to selectively inhibit RIP1 over RIP2,RIP3, or both RIP2 and RIP3. In some embodiments, a compound of thepresent disclosure can have a structure satisfying Formula I

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that the disclosed general formulasinclude within their scope all stereoisomers, N-oxides, tautomers,hydrates, solvates, isotopes, and/or prodrugs of compounds otherwisehaving structural features required by such formulas.

With reference to Formula I:

ring B is 5-membered or 6-membered heteroaryl;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, orC₃₋₆cycloalkyl); or

R¹ is a halogen, —C≡CH, or a -linker-R⁶ group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R^(b), —C(R^(f))₃,or —C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R⁵ independently are R^(e);

-   -   R^(a) is independently for each occurrence H or D (except for        embodiments where L is R^(a)), C₁₋₁₀aliphatic (such as        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),        C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆heterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or        —C(O)NR^(d)R^(d);    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can        be substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can be        substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can be        substituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can be        substituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can        be substituted with 1, 2 or 3 R^(e));    -   R^(d) is independently for each occurrence H; C₁₋₆alkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic        (which can be substituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl        (which can be substituted with 1, 2 or 3 R^(e)); C₅₋₁₀heteroaryl        (which can be substituted with 1, 2 or 3 R^(e)); or two R^(d)        groups together with the nitrogen bound thereto provide a        C₃₋₉heterocyclic (which can be substituted with one or more        R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one        or more R^(e));        -   R^(e) is independently for each occurrence halogen,            C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl,            C₃₋₆cycloalkyl, C₅₋₁₀heteroaryl, or —OR^(a); and        -   R^(f) is independently for each occurrence R^(a), R^(b), or            R^(e), or two R^(f) groups together with the carbon atom            bound thereto provide a C₃₋₆cycloalkyl group (which can be            substituted with one or more R^(e)), or a C₃₋₁₀heterocyclic            (which can be substituted with one or more R^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

p is 0, 1, 2, 3, 4, or 5.

In some embodiments, a compound of the present disclosure can have astructure satisfying Formula IA

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that the disclosed general formulasinclude within their scope all stereoisomers, N-oxides, tautomers,hydrates, solvates, isotopes, and/or prodrugs of compounds otherwisehaving structural features required by such formulas.

With reference to Formula IA:

ring B is 5-membered or 6-membered heteroaryl;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

R¹ is a halogen, —C≡CH, or a -linker-R⁶ group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R, —C(R^(f))₃, or—C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R⁵ independently are R^(e);

-   -   R^(a) is independently for each occurrence H or D (except for        embodiments where L is R^(a)), C₁₋₁₀aliphatic (such as        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),        C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆heterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or        —C(O)NR^(d)R^(d);    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can        be substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can be        substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can be        substituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can be        substituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can        be substituted with 1, 2 or 3 R^(e));    -   R^(d) is independently for each occurrence H; C₁₋₆alkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic        (which can be substituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl        (which can be substituted with 1, 2 or 3 R^(b)); C₅₋₁₀heteroaryl        (which can be substituted with 1, 2 or 3 R^(e)); or two R^(d)        groups together with the nitrogen bound thereto provide a        C₃₋₉heterocyclic (which can be substituted with one or more        R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one        or more R^(e));    -   R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₅₋₁₀heteroaryl, or —OR^(a); and    -   R^(f) is independently for each occurrence R^(a), R^(b), or        R^(e) or two R^(f) groups together with the carbon atom bound        thereto provide a C₃₋₆cycloalkyl group (and in some embodiments,        the C₃₋₆cycloalkyl group is substituted with one or more R^(e)),        or a C₃₋₁₀heterocyclic (and in some embodiments, the        C₃₋₁₀heterocyclic group is substituted with one or more R^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

p is 0, 1, 2, 3, 4, or 5.

In particular embodiments of Formulas I or IA, the 5-membered heteroarylgroup can have structure satisfying formula

wherein at least one W is nitrogen, and each remaining W independentlyis selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In someembodiments, the 5-membered heteroaryl group is a diazole, a triazole,an oxadiazole, or an oxazole. Exemplary triazoles include any of thefollowing:

Exemplary diazoles are selected from any of the following:

Exemplary oxazoles are selected from any of the following:

Exemplary oxadiazoles are selected from any of the following:

In particular embodiments of Formulas I or IA, L is oxygen or R^(a)wherein R^(a) is C₁-C₄alkyl, such as —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—. In some embodiments, L is —CH₂— or oxygen.

The linker group of R¹ groups where R² is linker-R⁶ is a C₁, C₂, C₃, orC₄ aliphatic group, such a C₂ alkyl group, an alkenyl group, or analkynyl group, or a C₁, C₂, C₃, or C₄ haloaliphatic group, such as a C₂haloalkyl group, or an haloalkenyl group. In some embodiments, thelinker group of R¹ is R^(a) wherein R^(a) is C₁-C₄alkyl, such as —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—; or the linker group isC₂-C₄alkenyl, such as —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, or —CH₂CH═CHCH₂—;or the linker group is C₂-C₄alkynyl, such as —C≡C—, —C≡CCH₂—, —CH₂C≡C—,or —CHC≡C—CH₂—. In some embodiments, the linker group isC₂-C₄haloalkenyl, such as —CF═CH—, —CCl═CH—, —CH═CCl—, —CH═CF—,—CCl═CCl—, —CF═CF—, or —CCl═CF—, —CF═CCl—. In some embodiments, linkergroup is is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—,—CCl═CH—, —CH═CCl—, or —C≡C—.

The R⁶ group of R¹ is C(R^(f))₃ in some embodiments, wherein one R^(f)is R^(e), wherein R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and eachother R^(f) independently is R^(a), wherein R^(a) is C₁₋₄aliphatic andpreferably each other R^(f) is R^(a) wherein R^(a) is independently foreach occurrence C₁₋₄alkyl. In particular embodiments, each other R^(f)is R^(a) wherein R^(a) is methyl or CD₃. In yet some additionalembodiments, R⁶ is —C(R^(f))₃ wherein each R^(f) is R^(a) wherein R^(a)is methyl or H or wherein each R^(f) is R^(a) wherein R^(a) is methyl orR^(b) wherein R^(b) is —C(O)OR^(c). In some additional embodiments, oneR^(f) is R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and the other twoR^(f) groups join together to provide a alicyclic (e.g., cyclopropane,cyclobutane, cyclopentane, or cyclohexane) or heterocyclic group (e.g.,epoxide, oxetane, tetrahydrofuran, tetrahydropyran, orhexahydrofuro[3,2-b]furan) with the carbon atom to which they are bound.In some such embodiments, the alicyclic and/or heterocyclic group can besubstituted, with some particular embodiments being substituted with oneor more hydroxyl groups or benzyl-carbonyl groups.

Some compound embodiments have a linker group that is a C₂-4 group,which can comprise an alkyne. In particular embodiments, R¹ is a-linker-R⁶ group and the linker is R^(a) wherein R^(a) is —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—, or —C≡C—, or —CH₂C≡C—,and R⁶ is R^(b) wherein R^(b) is —C(O)OEt or is —C(O)NR^(d)R^(d) or—NR^(d)R^(d) wherein each R^(d) independently for each occurrence ishydrogen, C₅₋₁₀heteroaryl, C₃₋₆cycloalkyl, or both R^(d) groups jointogether to provide a heterocyclic group with the nitrogen atom to whichthey are bound, which may further comprise one or more additionalheteroatoms aside from the nitrogen atom to which the R^(d) groups arebound. In some embodiments, one R^(d) is hydrogen and the other R^(d) isC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e), suchas one of the following:

R⁶ also can be R^(b) wherein R^(b) is —OH or —OR^(c) (wherein R^(c) isC₁₋₆alkyl and in some embodiments the C₁₋₆alkyl is substituted withC₅₋₁₀heteroaryl, such as pyridinyl; or wherein R^(c) is C₅₋₁₀heteroaryl,such as quinolinyl), or R^(b) can be —NR^(d)R^(d) wherein R^(d) isindependently for each occurrence H, C₅₋₁₀heteroaryl (and in someembodiments, the C₅₋₁₀heteroaryl group is substituted with one or moreR^(e) groups), or two R^(d) groups together with the nitrogen boundthereto provide a C₃₋₉heterocyclic (and in some embodiments, theC₃₋₉heterocyclic is substituted with one or more R^(e) groups) or aC₅₋₁₀heteroaryl (and in some embodiments, the C₅₋₁₀heteroaryl issubstituted with one or more R^(e) groups). In embodiments with R^(e)substitution, R^(e) independently for each occurrence C₅₋₁₀heteroaryl,or —OR^(a), wherein R^(a) is C₁₋₁₀alkyl.

Some compounds comprise a linker that is a C₁ group and an R⁶ group thatis R^(b), wherein R^(b) is —NR^(d)R^(d) wherein one R^(d) is H and theother R^(d) is pyridinyl, or wherein both R^(d) groups together with thenitrogen bound thereto provide a C₅₋₁₀heteroaryl; or R^(b) is OR^(c),wherein R^(c) is C₁₋₄alkyl substituted with a pyridinyl group. In someembodiments, R^(b) is

In some embodiments, R¹ can be selected from any of the following:

In some embodiments, each of R² and R³ independently is R^(a) whereinR^(a) is independently in each occurrence hydrogen, methyl, ethyl,propyl, butyl, pentyl, or hexyl. In particular embodiments, each of R²and R³ independently is R^(a) which is independently for each occurrencehydrogen, methyl, or ethyl. In exemplary embodiments, R² is methyl andR³ is hydrogen.

In some embodiments, each R⁴ independently and/or each R⁵ independentlyis R^(e), wherein R^(e) is alkyl, alkenyl, alkynyl, chloro, bromo, iodo,or fluoro. In particular embodiments, each R⁴ and/or each R⁵independently is R^(e) wherein R^(e) is lower aliphatic (e.g., methyl),fluoro, or chloro.

In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. Inparticular embodiments, m is 1, n is 0 and p is 0, 1, or 2.

The compounds of Formulas I or IA can also have structures satisfyingany one or more of Formulas II and IIA-IIF.

With reference to Formulas II and IIA-IIF, each of R¹ and R⁵ are asrecited above for Formulas I and/or IA. In particular embodiments, 0, 1,or 2 R⁵ groups are present. R⁵ can be R^(e) wherein R^(e) is fluoro orchloro. In other particular embodiments, R⁵ is not present. Withreference to Formulas IIA-IIF, each W independently is nitrogen oroxygen, and particularly nitrogen.

In some embodiments, the compounds of Formulas I or IA also can havestructures satisfying any one or more of Formulas III-VI:

With reference to Formulas III-VI, each R⁵ independently can be asrecited above and in some particular embodiments is lower aliphatic(e.g., methyl) or halogen, such as chloro or fluoro. Also, ring B is asrecited above and in some embodiments is selected from

R⁶ as illustrated in Formulas III-VI is as recited above and in someembodiments is selected from one of the following:

Certain disclosed exemplary compounds within the scope of one or more ofFormulas I, IA, II, IIA-IIF, and III-VI include:

Exemplary compounds within the scope of one or more of Formulas I, IA,II, IIA-IIF, and III-VI include:

-   I-1: Ethyl    (S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-2:    (S)—N-(7-(3-((1H-indazol-5-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-3:    (S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-4:    (S)-5-benzyl-N-(7-(3-((6,7-dimethoxyquinazolin-4-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-5: Ethyl    (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-6:    (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic    acid;-   I-7:    (S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-8: Ethyl    (S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-9:    (S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic    acid;-   I-10:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-11:    (S)-5-benzyl-N-(5-methyl-7-(3-morpholino-3-oxopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-12:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(quinolin-7-ylamino)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-13:    (S)-5-benzyl-N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-14:    (S)-5-benzyl-N-(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-15:    (S)-5-benzyl-N-(7-(4-hydroxybutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-16:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(pyridin-2-ylmethoxy)butyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-17:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(pyridin-2-ylamino)butyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-18:    (S)-1-(2,6-dichlorobenzyl)-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-19:    (S)—N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-20:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-21:    (S)-1-(2,6-dichlorobenzyl)-N-(5-methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-22:    (S,E)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-23:    (S,E)-5-benzyl-N-(7-(3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-24:    (S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-25:    (S)-1-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-26:    (S)-1-benzyl-N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-27:    (S)—N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-28:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-29:    (S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-30:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-31:    (S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-32:    (S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-33:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-34:    (S)-5-(2,4-difluorobenzyl)-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-35:    (S)-5-benzyl-N-(7-(5-hydroxypent-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-36:    (S)-5-benzyl-3-((7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide;-   I-37:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-38:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-39:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-40:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-41:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-42:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-43:    (S)-5-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-44:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-45:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-46:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-47:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-48:    (S)-1-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-49:    (S)-5-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-50:    (S)-1-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-51:    (S)-5-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-52:    (S)-1-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-53:    (S)-5-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-54:    (S)-1-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-55:    (S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-56:    (S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-57:    (S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-58:    (S)-1-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-59:    (S)-5-benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-60:    (S)-5-benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-61:    (S)-5-benzyl-N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-62:    (S)-1-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-63:    (S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-64:    (S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-65:    (S)-5-(2,6-dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-66:    (S)-5-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-67:    (S)-1-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-68:    (S)—N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-69:    (S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-70:    (R)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-71:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;-   I-72:    (S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-73:    (S)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-74:    (3S,3aR,6R,6aS)-6-(((S)-3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl    benzoate;-   I-75:    5-benzyl-N—((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-b]furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-76: methyl    (S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate;-   I-77:    (S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;-   I-78:    (S)-5-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-79:    (S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-80:    (S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-81:    (S)-5-benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-82:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-83:    (S)-1-([1,1′-biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-84:    (S)-1-(2,6-dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-85:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazole-3-carboxamide;-   I-86:    (S)-5-benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-87:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;-   I-88:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-89:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-90:    (S)-1-(2,6-dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-91:    (S)-5-benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-92:    (S)—N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-93:    (S)-5-benzyl-N-(7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-94:    (S,Z)-5-benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-95:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-96:    (S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;    or-   I-97:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

In some embodiments, one or more of the compounds can be included in apharmaceutical composition or medicament, and in some embodiments thecompound or compounds can be in the form of the parent compound or apharmaceutically acceptable salt, a stereoisomer, an N-oxide, atautomer, a hydrate, a solvate, an isotope, or a prodrug thereof. Thepharmaceutical composition typically includes at least one additionalcomponent other than a disclosed compound or compounds, such as apharmaceutically acceptable excipient, an adjuvant, an additionaltherapeutic agent (described in the following section), or anycombination thereof.

Pharmaceutically acceptable excipients can be included in pharmaceuticalcompositions for a variety of purposes, such as to dilute apharmaceutical composition for delivery to a subject, to facilitateprocessing of the formulation, to provide advantageous materialproperties to the formulation, to facilitate dispersion from a deliverydevice, to stabilize the formulation (e.g., antioxidants or buffers), toprovide a pleasant or palatable taste or consistency to the formulation,or the like. The pharmaceutically acceptable excipient(s) may include apharmaceutically acceptable carrier(s). Exemplary excipients include,but are not limited to: mono-, di-, and polysaccharides, sugar alcoholsand other polyols, such as, lactose, glucose, raffinose, melezitose,lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate andcitrate buffers; anti-adherents, such as magnesium stearate; binders,such as saccharides (including disaccharides, such as sucrose andlactose,), polysaccharides (such as starches, cellulose,microcrystalline cellulose, cellulose ethers (such as hydroxypropylcellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone,polyalkylene glycols); coatings (such as cellulose ethers, includinghydroxypropylmethyl cellulose, shellac, corn protein zein, and gelatin);release aids (such as enteric coatings); disintegrants (such ascrospovidone, crosslinked sodium carboxymethyl cellulose, and sodiumstarch glycolate); fillers (such as dibasic calcium phosphate, vegetablefats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calciumcarbonate, and magnesium stearate); flavors and sweeteners (such asmint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla;lubricants (such as minerals, exemplified by talc or silica, fats,exemplified by vegetable stearin, magnesium stearate or stearic acid);preservatives (such as antioxidants exemplified by vitamin A, vitamin E,vitamin C, retinyl palmitate, and selenium, amino acids, exemplified bycysteine and methionine, citric acid and sodium citrate, parabens,exemplified by methyl paraben and propyl paraben); colorants;compression aids; emulsifying agents; encapsulation agents; gums;granulation agents; and combinations thereof.

B. Combinations of Therapeutic Agents

The compounds described herein may be used alone, in combination withone another, in separate pharmaceutical compositions, together in asingle pharmaceutical composition, or as an adjunct to, or incombination with, other established therapies. The compound or compoundsor composition comprising the compound (or compounds) may beadministered once, or in plural administrations. In some embodiments,the compounds of the present invention may be used in combination withother therapeutic agents useful for the disorder or condition beingtreated. These other therapeutic agents may be administeredsimultaneously, sequentially in any order, by the same route ofadministration, or by a different route as the presently disclosedcompounds. For sequential administration, the compound(s) and thetherapeutic agent(s) may be administered such that an effective timeperiod of at least one compound and the therapeutic agent overlaps withan effective time period of at least one other compound and/ortherapeutic agent. In an exemplary embodiment of a combinationcomprising four components, the effective time period of the firstcomponent administered may overlap with the effective time periods ofthe second, third and fourth components, but the effective time periodsof the second, third and fourth components independently may or may notoverlap with one another. In another exemplary embodiment of acombination comprising four components, the effective time period of thefirst component administered overlaps with the effective time period ofthe second component, but not that of the third or fourth; the effectivetime period of the second component overlaps with those of the first andthird components; and the effective time period of the fourth componentoverlaps with that of the third component only. In some embodiments, theeffective time periods of all compounds and/or therapeutic agentsoverlap with each other.

In some embodiments, the compounds are administered with anothertherapeutic agent, such as an analgesic, an antibiotic, ananticoagulant, an antibody, an anti-inflammatory agent, animmunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with anti-canceror cytotoxic agents. Various classes of anti-cancer and anti-neoplasticcompounds include, but are not limited to, alkylating agents,antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, such as azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrmidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhbitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additionalcheckpoint inhibitors for combination with the compounds disclosedherein include, Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513).

The presently disclosed compounds also may be used advantageously withCAR-T therapies. Example of currently available CAR-T therapies areaxicabtagene ciloleucel and tisagenlecleucel.

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent compounds include proteasome inhibitors, such as bortezomib,carfilzomib, marizomib and the like.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude: Btk inhibitors, such as ibrutinib; CDK inhibitors, such aspalbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib; Mek inhibitors, such astrametinib; Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib; FLT-3 inhibitors, such as gilteritinib and quizartinib,P3-kinase inhibitors, such as idelalisib, Syk inhibitors, such asfostamatinib; and JAK inhibitors, such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected fromany of the following:

analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine,acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine,flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g.,ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides (e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies-anti-TNF-α antibodies, e.g., infliximab (Remicade™),adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;anticoagulants-warfarin (Coumadin™), acenocoumarol, phenprocoumon,atromentin, phenindione, heparin, fondaparinux, idraparinux,rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam,dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidalanti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine,mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors(COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac,famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen,indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone,naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants-mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues, forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

III. Methods of Making Compounds

The compounds can be prepared by any suitable method as will beunderstood by a person of ordinary skill in the art. One exemplarysuitable method is provided below with reference to specific compoundsin the examples, and can include the following first reaction stepaccording to Scheme 1.

With reference to Scheme 1, protected amine precursor 100 can be coupledwith R¹ group 102, which comprises an “R⁶-linker” group as illustratedin Scheme 1, using a metal-mediated, cross-coupling reaction to providethe cross-coupled product 104. In some embodiments, the metal-mediated,cross-coupling reaction can be carried out using a transition metalcatalyst, such as a palladium catalyst. Exemplary palladium catalystsinclude, but are not limited to, Pd(0) catalysts (e.g., Pd₂(dba)₃,Pd(dba)₂, Pd(PPh₃)₄, and the like) or Pd(II) catalyst (e.g., XPhos Pdgeneration 2 or generation 3, PdCl₂, Pd(OAc)₂, and the like). In someembodiments, the palladium catalyst can be used in combination withanother co-catalyst, such as CuI, to promote the cross-couplingreaction, such as in a Sonogoshira reaction. The metal-mediated,cross-coupling also can comprise using a base, such as an amine base(e.g., Et₃N), or an inorganic base (e.g., Cs₂CO₃, Na₂CO₃, K₂CO₃ or thelike), and a solvent (e.g., dimethylformamide). With reference to Scheme1, X is a suitable group for metal-mediated, cross-coupling, such as ahalogen or a triflate group and PG is an amine protecting group, whichcan be selected from, but is not limited to, a9-fluorenylmethoxycarbonyl (“Fmoc”) group, a t-butyloxycarbonyl (“Boc”)group, a trityl (“Tr”) group, an allyloxycarbonyl (“Alloc”) group, abenzyloxycarbonyl (“Cbz”) group, and the like.

Representative examples of the method steps shown in Scheme 1 areprovided below in Schemes 2A-2F. A method similar to that illustrated inScheme 2A can be used to make compounds I-14 to I-17 and I-35 byreplacing the propargylic alcohol in Scheme 2A with the correspondingalkyne group that gives rise to each of compounds I-14 to I-17 and I-35;the further modifications that can be used to arrive at the finalstructure of compounds I-14 to I-17 are discussed below.

Once cross-coupled product 104 is made, it can be subjected to anoptional linker group reduction step wherein linker groups comprisingone or more sites of unsaturation can be reduced to saturated linkergroups and/or linker groups having fewer degrees of unsaturation. If alinker reduction group is used, it can then be followed by adeprotection step and then an amide formation step, as illustrated inScheme 3. Alternatively, if a linker group reduction step is not used,then cross-coupled product 104 can be deprotected and converted to amidecompound 302.

With reference to Scheme 3, an optional linker reduction step can becarried out. For example, if the linker comprises a site of unsaturation(e.g., a double or triple bond), the site of unsaturation can be reducedsuch that it becomes fully saturated (e.g., such as reducing a doublebond and/or a triple bond to a single bond) or that it has few degreesof unsaturation (e.g., such as reducing a triple bond to a double bond).Suitable reagents for carrying out such an optional linker reductionstep are recognized by those of ordinary skill in the art with thebenefit of the present disclosure; however, one exemplary set ofconditions includes exposing cross-coupled product 104 to H₂ in thepresence of Pd on carbon. As these steps are optional, they need not becarried out in all embodiments. Instead, in some embodiments,cross-coupled product 104 can be deprotected to provide an amine that isthen converted to amide compound 302 by reacting the amine with asuitable acid coupling partner 300, as illustrated in Scheme 3.

Representative examples of the method steps shown in Scheme 3 areprovided below in Schemes 4A-4M. A method similar to that described inScheme 4A can be used to make compounds I-14 to I-17. Compounds I-16 andI-17 can be further functionalized as discussed below.

In some embodiments, the method can further comprise making one or moreadditional modifications to amide compound 302 to provide amide compound500, such as modifying an R⁶ group to form a different R⁶ group, asillustrated in Scheme 5.

With reference to Scheme 5, one or more modifications to the R⁶ groupcan be carried out. For example, if R⁶ is an ester group, it can beconverted to a carboxylic acid or to a primary alcohol. Suitablereagents for carrying out such an optional modification step arerecognized by those of ordinary skill in the art with the benefit of thepresent disclosure; however, one exemplary set of conditions includesexposing an R⁶ ester group to LiOH to provide the corresponding acid,such as is illustrated in Schemes 6A-6E below. The resulting acid caneven be further modified to provide an amide-containing product by usingsuitable amide coupling conditions (such as those described above) incombination with an amine coupling partner, such as is illustrated inSchemes 6A-6E. Similar methods can be used to make compounds I-10, I-11,I-13, I-18, I-19, I-26, I-27, I-33, I-34, and I-22 and I-23 (wherein thedouble bond of the linker group is not first reduced prior to coupling).In yet additional embodiments, compounds I-16 and I-17 can be made byconverting the terminal alcohol obtained in the above-described methodsinto a functionalized alcohol, such as for compound I-16, or to anamine, such as for compound I-17.

IV. Methods of Using Compounds

A. Diseases/Disorders

The disclosed compounds, as well as combinations and/or pharmaceuticalcompositions thereof, may be used to inhibit a RIP1 kinase by contactingthe kinase either in vivo or ex vivo, with a compound or compounds ofthe present disclosure, or a composition comprising a compound orcompounds of the present disclosure. Disclosed compound or compounds, orcompositions comprising a disclosed compound or compounds also can beused to ameliorate, treat or prevent a variety of diseases and/ordisorders. In particular embodiments, the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, may be useful for treating conditions in which inhibition ofRIP1 or a pathway involving RIP1 is therapeutically useful. In someembodiments, the compounds directly inhibit RIP1 kinase activity. Incertain embodiments, disclosed compounds are useful for treatingauto-immune diseases, inflammatory disorders, cardiovascular diseases,nerve disorders, neurodegenerative disorders, allergic disorders,respiratory diseases, kidney diseases, cancers, ischemic conditions,erythrocyte deficiencies, lung and brain injuries (e.g., induced byischemia-reperfusion or cisplatin and/or cerebrovascular accident), andbacterial and viral infections.

In some embodiments, the disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treator prevent allergic diseases, amyotrophic lateral sclerosis (ALS),spinal muscular atrophy, systemic lupus erythematosus, rheumatoidarthritis, type I diabetes mellitus, inflammatory bowel disease, biliarycirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunemyositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy,or asthma.

The disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, may also be useful for treatingimmune regulatory disorders related to bone marrow or organ transplantrejection or graft-versus-host disease. Examples of inflammatory andimmune regulatory disorders that can be treated with the compounds (orpharmaceutical compositions or combinations thereof) include, but arenot limited to, transplantation of organs or tissue, graft-versus-hostdiseases brought about by transplantation, autoimmune syndromesincluding rheumatoid arthritis, systemic lupus erythematosus,Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis,systemic inflammatory response syndrome, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,ischemia-reperfusion injuries, inflammatory bowel diseases, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn'sdisease, ulcerative colitis, migraine, rhinitis, eczema, interstitialnephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabeticnephropathy, multiple myositis, Guillain-Barre syndrome, Meniere'sdisease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis or myocardial infarction, scleroderma (includingsystemic scleroderma), anti-phospholipid syndrome, Wegener's granuloma,Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, corneal alkali burn, dermatitis erythema multiforme, linearIgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis,sepsis, pancreatitis, diseases caused by environmental pollution, aging,carcinogenesis, metastasis of carcinoma and hypobaropathy, diseasecaused by histamine or leukotriene-C4 release, Behcet's disease,autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis,partial liver resection, acute liver necrosis, necrosis caused by toxin,viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-Bhepatitis, cirrhosis, alcoholic liver disease, including alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity,hepatotoxicity, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, chronic kidneydiseases, kidney damage/injury (caused by, for example, nephritis, renaltransplant, surgery, administration of nephrotoxic drugs, acute kidneyinjury), augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, Parkinson'sdisease, trauma, or chronic bacterial infection.

In certain embodiments the present compounds are useful for treatingnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the compounds are useful for treatinginterleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, lysosomal storage diseases (e.g.,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sach disease, andWolman disease).

In certain embodiments, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, are usefulfor treating and/or preventing rheumatoid arthritis, psoriaticarthritis, osteoarthritis, systemic lupus erythematosus, lupusnephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis,multiple sclerosis, psoriasis, in particular pustular psoriasis, type Idiabetes, type II diabetes, inflammatory bowel disease (Crohn's diseaseand ulcerative colitis), hyperimmunoglobulinemia d and periodic feversyndrome, cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, systemic juvenile idiopathic arthritis, adult's onset Still'sdisease, gout, gout flares, pseudogout, sapho syndrome, Castleman'sdisease, sepsis, stroke, atherosclerosis, celiac disease, DIRA(deficiency of Il-1 receptor antagonist), Alzheimer's disease,Huntington's disease, or Parkinson's disease.

Proliferative diseases that may be treated by the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, include benign or malignant tumors, solid tumor, carcinoma ofthe brain, kidney, liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin,bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiplemyeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88driven disorder (such as ABC diffuse large B-cell lymphoma (DLBCL),Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma or chronic lymphocytic leukemia), smoldering or indolentmultiple myeloma, or hematological malignancies (including leukemia,acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocyticleukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma,Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplasticsyndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma,Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma,multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). Inparticular, the presently disclosed compounds are useful in treatingdrug resistant malignancies, such as those resistant to JAK inhibitorsibrutinib resistant malignancies, including ibrutinib resistanthematological malignancies, such as ibrutinib resistant CLL andibrutinib resistant Waldenström's macroglobulinemia.

Examples of allergic disorders that may be treated using the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, include, but are not limited to, asthma (e.g.atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma,non-atopic asthma, bronchial asthma, non-allergic asthma, essentialasthma, true asthma, intrinsic asthma caused by pathophysiologicdisturbances, essential asthma of unknown or unapparent cause,emphysematous asthma, exercise-induced asthma, emotion-induced asthma,extrinsic asthma caused by environmental factors, cold air inducedasthma, occupational asthma, infective asthma caused by or associatedwith bacterial, fungal, protozoal, or viral infection, incipient asthma,wheezy infant syndrome, bronchiolitis, cough variant asthma ordrug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA),allergic rhinitis, perennial allergic rhinitis, perennial rhinitis,vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis,acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoidsinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treat,ameliorate or prevent any one, several or all of these symptoms of RA.Thus, in the context of RA, the compounds are considered to providetherapeutic benefit when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising one or more active compounds ofthe invention may be manufactured by any suitable method, such asmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilization processes. Thepharmaceutical compositions may be formulated using one or morephysiologically acceptable excipients (e.g., diluents, carriers, orauxiliaries), one or more adjuvants, or combinations thereof to providepreparations which can be used pharmaceutically.

The active compound(s) may be formulated in the pharmaceuticalcompositions per se, or in the form of a pharmaceutically acceptablesalt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, anisotope, or a prodrug thereof. Typically, such salts are more soluble inaqueous solutions than the corresponding free acids and bases, but saltshaving lower solubility than the corresponding free acids and bases mayalso be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceuticallyacceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate,isotope, or prodrug may be formulated as solutions, gels, ointments,creams, suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thepharmaceutical compositions may also contain formulating agents, such assuspending, stabilizing and/or dispersing agent. The formulations forinjection may be presented in unit dosage form, e.g., in ampules or inmultidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable excipients such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound, as is well known.

For buccal administration, the pharmaceutical compositions may take theform of tablets or lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), pharmaceutically acceptable salt,stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrugcan be conveniently delivered in the form of an aerosol spray frompressurized packs or a nebulizer with the use of a suitable propellant,e.g.,) dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound (0.5 20 mg/ml);benzalkonium chloride (0.1 0.2 mg/mL); polysorbate 80 (TWEEN® 80; 0.5 5mg/ml); carboxymethylcellulose sodium or microcrystalline cellulose (115 mg/ml); phenylethanol (14 mg/ml); and dextrose (20 50 mg/ml). The pHof the final suspension can be adjusted to range from about pH 5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mL of thedisclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mMcitrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as asolution, emulsion, suspension, etc. suitable for administration to theeye. A variety of vehicles suitable for administering compounds to theeye are known in the art. Specific non-limiting examples are describedin U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445;5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851,which are incorporated herein by reference.

For prolonged delivery, the active compound(s) can be formulated as adepot preparation for administration by implantation or intramuscularinjection. The active ingredient maybe formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s). Certain organicsolvents, such as dimethylsulfoxide (DMSO), may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

C. Dosages

The disclosed compound, pharmaceutical compositions, or combinations ofdisclosed compounds will generally be used in an amount effective toachieve the intended result, for example, in an amount effective toinhibit a RIP1 kinase and/or to treat, prevent or ameliorate aparticular condition. The disclosed compound(s), or pharmaceuticalcompositions thereof, can be administered therapeutically to achievetherapeutic benefit or prophylactically to achieve a prophylacticbenefit. Therapeutic benefit means eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

As known by those of ordinary skill in the art, the preferred dosage ofdisclosed compounds may depend on various factors, including the age,weight, general health, and severity of the condition of the patient orsubject being treated. Dosage also may need to be tailored to the sex ofthe individual and/or the lung capacity of the individual, whenadministered by inhalation. Dosage may also be tailored to individualssuffering from more than one condition or those individuals who haveadditional conditions that affect lung capacity and the ability tobreathe normally, for example, emphysema, bronchitis, pneumonia,respiratory distress syndrome, chronic obstructive pulmonary disease,and respiratory infections. Dosage, and frequency of administration ofthe disclosed compound(s) or pharmaceutical compositions thereof, willalso depend on whether the disclosed compound(s) are formulated fortreatment of acute episodes of a condition or for the prophylactictreatment of a disorder. A person of ordinary skill in the art will beable to determine the optimal dose for a particular individual.

For prophylactic administration, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient or subject at risk of developing one of thepreviously described conditions. For example, if it is unknown whether apatient or subject is allergic to a particular drug, the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can be administered prior to administration of thedrug to avoid or ameliorate an allergic response to the drug.Alternatively, prophylactic administration can be used to avoid orameliorate the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a disclosed compound(s), orpharmaceutical composition thereof, can be administered to an allergysufferer prior to expected exposure to the allergen. A disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can also be administered prophylactically tohealthy individuals who are repeatedly exposed to agents known to one ofthe above-described maladies to prevent the onset of the disorder. Forexample, a disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, can be administered to a healthyindividual who is repeatedly exposed to an allergen known to induceallergies, such as latex, in an effort to prevent the individual fromdeveloping an allergy. Alternatively, a disclosed compound, combinationsof disclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 μM, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM,from greater than 0 to 0.1 μM, or from greater than 0 to 0.05 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

In some embodiments, assays suitable for determining RIP1 activity canbe used. Such assay methods can be used to evaluate the efficacy ofcompound embodiments disclosed herein and/or that can be used todetermine amounts/dosages of the compound embodiments that can provide adesired efficacy. In some embodiments, the assay can be an ADP-Glo™assay that assesses the ability of a compound embodiment to inhibitRIP1. In other embodiments, whole cell assays using mouse and/or humancells, such as U937 and/or L929 cell necroptosis assays, can beperformed to determine safe and effective doses of compounds that can beused in human in vivo studies. Using these whole cell assays, thecompound's activity against human and/or murine RIP1 can be assessed inan in vitro context, which then allows a person of ordinary skill in theart to determine safe and effective dosages for in vivo use. Yet anotherassay that can be used to evaluate the activity of compound embodimentsdescribed herein to treat a disease or condition involving RIP1 is anacute hypothermia mouse model, which assesses the compound's ability toinhibit TNF-alpha induced hypothermia. Each of these assays, and variousresults from using these assays, are described in detail in the Examplessection of the present disclosure.

Dosage amounts of disclosed compounds will typically be in the range offrom greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or 0.001mg/kg/day or 0.01 mg/kg/day, up to at least about 100 mg/kg/day. Moretypically, the dosage (or effective amount) may range from about 0.0025mg/kg to about 1 mg/kg administered at least once per day, such as from0.01 mg/kg to about 0.5 mg/kg or from about 0.05 mg/kg to about 0.15mg/kg. The total daily dosage typically ranges from about 0.1 mg/kg toabout 5 mg/kg or to about 20 mg/kg per day, such as from 0.5 mg/kg toabout 10 mg/kg per day or from about 0.7 mg/kg per day to about 2.5mg/kg/day. Dosage amounts can be higher or lower depending upon, amongother factors, the activity of the disclosed compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the disclosed compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Pharmaceutical compositions comprising one or more of the disclosedcompounds typically comprise from greater than 0 up to 99% of thedisclosed compound, or compounds, and/or other therapeutic agent bytotal weight percent. More typically, pharmaceutical compositionscomprising one or more of the disclosed compounds comprise from about 1to about 20 total weight percent of the disclosed compound and othertherapeutic agent, and from about 80 to about 99 weight percent of apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition can further comprise an adjuvant.

Preferably, the disclosed compound, combinations of disclosed compounds,or pharmaceutical compositions thereof, will provide therapeutic orprophylactic benefit without causing substantial toxicity. Toxicity ofthe disclosed compound can be determined using standard pharmaceuticalprocedures. The dose ratio between toxic and therapeutic (orprophylactic) effect is the therapeutic index. Disclosed compounds thatexhibit high therapeutic indices are preferred.

V. Examples Example 1

Compounds of the present disclosure can be made using a suitablestarting compound, such as compound 200 or compound 206, illustrated inthe schemes above. A representative method for making compound 200 isillustrated in Scheme 7A and a representative method for making compound206 is illustrated in Scheme 7B.

Spectral Characterization for3-(S)—N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200)

¹H nmr (400 MHz, CDCl₃) δ 7.41-7.38 (6H, m, 6H of C(C₆H₅)₃), 7.25-7.15(10H, m, oxobenzoxazapineH-8, 9H of C(C₆H₅)₃), 7.00 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.37 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.53 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH₃).

Characterization data and particular methods of making representativecompounds disclosed herein are provided below.

Example 2

Synthesisof(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

A mixture of the bromooxazapine (0.210 g, 0.410 mmol, 1.0 eq) potassiumcarbonate (0.566 g, 4.101 mmol, 10.0 eq) and copper(I) iodide (0.008 g,0.041 mmol, 0.1 eq) in dimethylformamide (3.0 mL) was degassed bybubbling argon through for five minutes. 2-Methyl-2-hydroxybut-3-yne(0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq) andtetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 eq)were added and the reaction sealed before heating in the microwave to120° C. for 1 hour. The reaction was partitioned between EtOAc (80 mL)and water (80 mL). The organics were washed with brine (80 mL), water(80 mL) and brine (80 mL), dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (10→80% EtOAc-hexane) yielded the starting material(0.091 g) and the title compound (0.079 g) as a colorless oil; ¹H nmr(400 MHz, CDCl₃) δ 7.40-7.38 (6H, m, 6H of C(C₆H₅)₃), 7.24-7.7.14 (9H,m, 9H of C(C₆H₅)₃), 7.13 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8),6.96 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 6.95 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.55 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 2.78 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂); m/z:555 [M+K]⁺, 243 [C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group

To a solution of the trityl protected amine (0.079 g, 0.153 g, 1.0 eq)in dioxane (2.0 mL) was added a solution of hydrogen chloride (0.15 mLof a 4M solution in dioxane, 0.614 mmol, 4.0 eq). The reaction wasstirred at room temperature for 6 hours before concentrating to drynessto obtain a white solid, which was used without purification; m/z: 275[M+H]⁺.

Synthesisof(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of the aminooxobenzoxazapine hydrochloride (0.076 mmol,1.0 eq) and benzyltriazole carboxylic acid (0.017 g, 0.084 mmol, 1.1 eq)in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033mL, 0.190 mmol, 2.5 eq) followed by HATU (0.032 g, 0.084 mmol, 1.1 eq).The reaction was stirred at room temperature for 4 hours and partitionedbetween EtOAc—CH₂Cl₂ (5:1, 60 mL) and NaHCO₃ (60 mL). The organics werewashed with brine (50 mL), water (50 mL) and brine (50 mL), dried(Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10%MeOH—CH₂Cl₂) yielded the title compound as a white solid; ¹H nmr (400MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.22 (7H, m, 7×ArH), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CCH ₂C₆H₅), 3.40 (3H, s, NCH₃), 1.63(6H, s, C(CH ₃)₂OH); m/z: 442 [M+H—H₂O]⁺.

Similar steps as those above for Example 2 can be used to make compoundsI-14, to I-17, and I-35.

Example 3

Synthesis of ethyl(S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylate

To a suspension of tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(0.500 g, 1.35 mmol, 1.0 eq) in dimethylformamide (8 mL) was degassed bybubbling argon through for five minutes. Ethyl acrylate (0.270 g, 0.29mL, 2.70 mmol, 2.0 eq) and triethylamine (0.272 g, 0.37 mL, 2.0 eq) wereadded followed by tetrakis(triphenylphosphine (0.156 g, 0.14 mmol, 0.1eq). The reaction was sealed and heated in the microwave to 100° C. for1 hour and 120° C. for 1 hour. The reaction was partitioned betweenEtOAc (100 mL) and water (100 mL). The organics were washed with brine(70 mL), water (100 mL) and brine (70 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (10→40%EtOAc-hexane) yielded the title compound (0.250 g, %) as a yellow foam;¹H nmr (400 MHz, CDCl₃) δ 7.62 (1H, d, J 16.0 Hz, ArCH═CHCO), 7.35 (1H,dd, J 8.0, 2.0 Hz, oxobenzoxazepineH-8), 7.33 (1H, d, J 2.0 Hz,oxobenzoxazepineH-6), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepineH-9), 6.37(1H, d, J 16.0 Hz, ArCH═CHCO), 5.49 (1H, d, J 7.0 Hz, NH), 4.65 (1H, dt,J 11.0, 7.0 Hz, oxobenzoxazepineH-3), 4.57 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.27 (2H, q, J 7.0 Hz, OCH ₂CH₃), 4.19 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepineH-2), 3.41 (3H, s, NCH₃), 1.39 (9H,s, C(CH₃)₃), 1.34 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z: 291 [M+H—CO₂—C₄H]⁺.

Synthesis ofethyl(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

A solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq) inethyl acetate (20 mL) was added palladium on carbon (0.23 g). Thereaction was purged with hydrogen and stirred under an atmosphere ofhydrogen for 14 hours. The reaction was purged with nitrogen andfiltered through Celite®, eluting with ethyl acetate (2×20 mL). Thefiltrate was concentrated under reduced pressure; ¹H nmr (400 MHz,CDCl₃) δ 7.04-6.82 (3H, m, oxobenzoxazepineH-6, H-8, H-9), 5.50 (1H, d,J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.52(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.14-4.07 (1H, m, 1Hof oxobenzoxazepineH-2), 4.12 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.36 (3H, s,NCH₃), 2.91 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 2.59 (2H, t, J 7.5 Hz,2H of ArCH₂CH₂CO), 1.37 (9H, s, C(CH₃)₃), 1.23 (3H, t, J 7.0 Hz,OCH₂CH₃); m/z: 337 [M+H—C₄H₈]⁺, 293 [M+H—CO₂—C₄H₈]⁺. The crude materialwas dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL ofa 4M solution in dioxane, 3.21 mmol, 5.0 eq). The reaction was stirredat room temperature for 14 hours before adding further hydrogen chloridesolution (0.8 mL, 5.0 eq). After stirring for a further 2 hours thereaction was concentrated under reduced pressure and dried under vacuumto obtain a brown solid. The crude material was used without furtherpurification; m/z: 293 [M+H]⁺.

Synthesis of ethyl(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

Huorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq) was added to asolution of the ethyl(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate(0.140 g, 0.477 mmol, 1.0 eq) and diisopropylethylamine (0.154 g, 0.21mmol, 2.5 eq) in dimethylformamide (5.0 eq). HATU (0.199 g, 0.525 mmol,1.1 eq) was added and the reaction stirred at 0° C. for 1 hour and roomtemperature for 1 hour. The reaction was partitioned between EtOAc (120mL) and NaHCO₃-water (1:1, 120 mL). The organics were washed with brine(100 mL), water (100 mL) and brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (40→80%EtOAc-hexane) yielded the title compound 0.138 mg) as a white solid; ¹Hnmr (400 MHz, CDCl₃) δ 8.11 (1H, s, triazoleH-5), 8.05 (1H, d, 7.0 Hz,NH), 7.38-7.30 (2H, m, 2H of C₆H₄F), 7.26-7.07 (6H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-7, H-8, H-9), 5.42 (2H, s, CH ₂C₆H₄F), 5.08 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); ¹³C nmr (100 MHz, CDCl₃) δ168.9, 160.6 (d, J 248.5 Hz), 158.3, 156.7, 150.1, 144.1 (d, J 2.0 Hz),136.0, 131.1 (d, J 8.5 Hz), 130.9 (d, J 2.5 Hz), 127.6, 125.7, 124.9 (d,J Hz), 123.3, 123.1, 121.2 (d, J 14.0 Hz), 115.8 (d, J 21.5 Hz), 77.3,49.2, 47.9 (d, J 4.0 Hz), 35.5; ¹⁹F nmr (380 MHz, CDCl₃) δ −118.1; m/z:518 [M+Na]⁺, 496 [M+H]⁺ (found [M+H]⁺, 496.1991, C₂₅H₂₆FN₅O₅ requires[M+H]⁺ 496.1973).

Similar steps as those above for Example 3 and those below for Examples4 and 5 can be used to make compounds I-10, I-11, I-13, I-18, I-19,I-26, I-27, I-33, I-34, and I-22 and I-23 (wherein the double bond ofthe linker group is not first reduced prior to coupling).

Example 4

Synthesis of(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicAcid

To a solution of the ethyl ester (0.103 g, 0.208 mmol, 1.0 eq) intetrahydrofuran (3 mL) was added aqueous lithium hydroxide (0.017 g,0.416 mmol, 2.0 eq in 1 mL of water). The reaction was stirred at roomtemperature for 3 hours before partitioning between EtOAc (80 mL) andNH₄Cl (80 mL). The aqueous phase was extracted with EtOAc (2×60 mL). Thecombined organics were washed with brine (80 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (0→10%MeOH—CH₂C₂) yielded the title compound 0.054 g, %) was a white solid; ¹Hnmr (400 MHz, CDCl₃) δ 8.12 (1H, s, triazoleH-5), 8.04 (1H, d, J 7.5 Hz,NH), 7.40-7.30 (2H, m, 2×ArH), 7.16 (1H, dd, J 7.5, 1.0 Hz, 1×ArH),7.14-7.10 (2H, m, 2×ArH), 7.07 (2H, m, 2×ArH), 5.43 (2H, s, NCH ₂C₆H₅F),5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.73 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazepineH-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazepineH-2), 3.41 (3H, s, NCH₃), 2.96 (2H, t, J 7.5 Hz, 2H ofArCH₂CH₂CO), 2.70 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO); ¹⁹F nmr (CDCl₃) δ−118.1 (dd, J 16.5, 7.0 Hz); m/z: 468 [M+H]⁺ (found [M+H]⁺, 468.1688,C₂₃H₂₂FN₅O₅ requires [M+H]⁺ 468.1678).

Example 5

Synthesisof(S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A solutionof(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicacid (0.049 g, 0.105 mmol, 1.0 eq) and 6-aminoindazole (0.017 g, 0.126mmol, 1.2 eq) in dimethylformamide (10 mL) was cooled to 0° C.Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 eq) was addedfollowed by HATU (0.048 g, 0.126 mmol, 1.2 eq) and the reaction stirredat 0° C. for 1 hour and room temperature for 2 hours. The reaction waspartitioned between EtOAc (50 mL) and NaHCO₃ (50 mL). The organics werewashed with brine (50 mL). The combined aqueous phase was extracted withEtOAc (20 mL). The combined organics were washed with water (50 mL) andbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure.Column chromatography (0→10% MeOH—CH₂Cl₂) yielded the title compound(0.xx g, %) yielded the title compound as a white solid; ¹H nmr (400MHz, CDCl₃) δ 8.12 (1H, s, triazoleH-5), 8.00 (1H, d, J 7.5 Hz, NH),7.94 (1H, d, J 0.5 Hz, indazoleH-3), 7.90 (1H, s, NH), 7.83 (1H, m,indazoleH-7), 7.57 (1H, d, J 9.0 Hz, indazoleH-4), 7.37-7.30 (2H, m, 2Hof C₆H₄F), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H of C₆H₄F), 7.09-7.00 (5H, m,indazoleH-5, 1H of C₆H₄F, oxobenzoxazepineH-6, H-7, H-9), 5.40 (2H, s,NCH ₂C₆H₄F), 5.02 (1H, td, J 11.5, 7.5 Hz, oxobenzoxazepineH-3), 4.63(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.23 (1H, dd, J11.5, 9.5 Hz, 1H of oxobenzoxazepineH-2), 3.29 (3H, s, NCH₃), 3.03 (2H,t, J 7.0 Hz, ArCH ₂CH₂CON), 2.68 (2H, m, ArCH₂CH ₂CON); ¹³C nmr (CDCl₃)δ 170.6, 168.7, 160.7 (d, J 248.5 Hz), 158.8, 156.4, 148.4, 144.4,140.6, 138.5, 136.3, 135.9, 134.3, 131.2 (d, J 8.5 Hz), 131.0 (d, J 3.0Hz), 127.5, 124.9 (d, J 4.0 Hz), 123.4, 122.9, 121.1, 121.0, 120.3,115.8 (d, J 20.5 Hz), 115.3, 101.1, 77.2, 49.1, 48.0 (d, J 4.0 Hz),39.3, 35.3, 31.1; ¹⁹F nmr (CDCl₃) δ −118.0; m/z: 583 [M+H]⁺ (found[M+H]⁺, 583.2205, C₃₀H₂₇FN₈O₄ requires [M+H]⁺ 583.2212).

Example 6

Ethyl(S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.96 (1H, s,triazoleH-5), 7.42 (2H, m, 2×ArH), 7.32 (1H, dd, J 9.0, 7.0 Hz, 1×ArH),7.10 (1H, m, 1×ArH), 7.06 (2H, dd, J 6.0, 2.0 Hz, 2×ArH), 5.70 (2H, s,CH₂C₆H₃Cl₂), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.74(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.21 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepineH-2), 4.14 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.41 (3H, s, NCH₃), 2.95 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO),2.63 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 1.24 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 172.5, 168.9, 158.3, 156.5, 148.4, 143.9,138.4, 136.9, 135.8, 131.4, 129.1, 128.9, 127.5, 123.2, 122.9, 77.2,60.6, 49.4, 49.3, 35.7, 35.5, 30.3, 14.2; m/z: 548, 546 [M+H]+(found[M+H]⁺, 546.1291, C₂₅H₂₅C₁₂N₅O₅ requires [M+H]⁺ 546.1306).

Example 7

(S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicAcid

¹H nmr (400 MHz, CDCl₃) δ 8.13 (1H, d, J 7.5 Hz, NH), 7.32-7.22 (5H, m,5×ArH), 7.08-7.06 (3H, m, 3×ArH), 4.97 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.38 (3H, s, NCH₃), 2.94(2H, m, 2H of ArCH ₂CH ₂CO₂H), 2.70 (2H, m, 2H of ArCH ₂CH ₂CO₂H); ¹⁹Fnmr (CDCl₃) δ −118.1; m/z: 450 [M+H]⁺ (found [M+H]⁺, 450.1760,C₂₃H₂₃N₅O₅ requires [M+H]⁺ 450.1772).

Example 8

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.29-7.21 (5H, m,5×ArH), 7.10-7.07 (3H, m, 3×ArH), 5.05 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH₂Ph), 3.45 (2H, t, J 7.0 Hz, 2H ofpyrrolidine), 3.38 (3H, s, NCH3), 3.35 (2H, m, 2H of pyrrolidine), 2.97(2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.57 (2H, t, J 7.5 Hz, 2H ofArCH2CH2CO), 1.92 (2H, m, 2H of pyrrolidine), 1.83 (2H, m, 2H ofpyrrolidine); ¹³C nmr (100 MHz, CDCl₃) δ 170.4, 168.9, 158.5, 148.2,139.5, 135.9, 135.7, 128.9, 128.8, 127.6, 127.1, 123.5, 122.7, 77.1.49.2, 46.6, 45.8, 36.6, 35.5, 33.2, 30.4, 26.0, 24.4; m/z: 503 [M+H]⁺(found [M+H]⁺, 503.2403, C₂₇H₃₀N₆O₄ requires [M+H]⁺ 503.2401).

Example 9

Synthesis of(S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylamide

To a mixture of the bromooxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq)and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) was added dimethylformamide(5 mL) and the mixture degassed by bubbling argon through for fiveminutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was addedfollowed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq) and the reactionsealed and heated to 120° C. in the microwave for 1 hour. The reactionwas partitioned between EtOAc (100 mL) and NaHCO₃ (100 mL). The organicswere washed with brine (80 mL), water (100 mL) and brine (80 mL) dried(Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10%MeOH—CH₂Cl₂) yielded the title compound (0.267 g, 91%) as a pale yellowsolid; ¹H nmr (400 MHz, CDCl₃) δ 7.55 (1H, d, J 15.5 Hz, ArCH═CHCO),7.39-7.36 (7H, m, 6H of C(C₆H₅)₃, oxobenzoxazapineH-8), 7.25-7.13 (9H,m, 9H of C(C₆H₅)₃), 7.01 (1H, d, J 8.5 Hz, oxobenzoxazepineH-9), 6.97(1H, d, J 2.0 Hz, oxobenzoxazepineH-6), 6.39 (1H, d, J 15.5 Hz,ArCH═CHCO), 5.95 (2H, br s, NH₂), 4.51 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazepineH-2), 3.54 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.31 (1H, d, J 8.5 Hz, NH), 2.94 (3H, s, NCH₃);m/z: 526 [M+Na]⁺, 243 [C(C₆H₅)₃]⁺.

Synthesisof(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide

A solution of the α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0eq) in ethyl acetate-methanol (5:2, 7 mL) was purged with nitrogen andpalladium on carbon (0.100 g) added. The reaction was purged withhydrogen and stirred under an atmosphere of hydrogen for 2 hours. Thereaction was purged with nitrogen and filtered through celite, elutingwith EtOAc (30 mL). The filtrate was concentrated under reducedpressure. The residue was dissolved in dioxane (5 mL) and hydrogenchloride (0.66 mL of a 4M solution in dioxane, 2.659 mmol, 5.0 eq)added. The reaction was stirred at room temperature for 6 hours, a whitesolid formed. The reaction was concentrated to dryness and used withoutpurification; m/z: 265 [M+H]⁺.

Synthesis of(S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide

To a mixture of the aminooxobenzoxazapine hydrochloride (0.134 mmol, 1.0eq) and the benzyltriazole carboxylic acid (0.033 g, 0.161 mmol, 1.2 eq)in dimethylformamide (1.0 mL) was added diisopropylethylamine (0.043 g,0.058 mL, 0.335 mmol, 2.5 eq) followed by HATU (0.102 g, 0.268 mmol, 2.0eq). The reaction was stirred at room temperature for 4 hours andpartitioned between EtOAc—CH₂Cl₂ (5:1, 60 mL) and water (60 mL). Theorganics were washed with brine (50 mL), water (60 mL) and brine (50mL). The organics were dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the title compound as a whitesolid; ¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.36-7.28(5H, m, 5×ArH), 7.11-7.06 (3H, m, 3×ArH), 5.44 (2H, br s, CONH₂), 5.02(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 2.99(2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 2.54 (2H, t, J 7.5 Hz, 2H ofArCH₂CH₂CO); m/z: 449 [M+H]⁺.

Example 10

Formation of(S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

Dioxane (4 mL) and water (2 mL) were added to a mixture of thebromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq),7-((trifluoro-λ⁴-boraneyl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine,potassium salt (0.180 g, 0.738 mmol, 1.4 eq) and caesium carbonate(0.515 g, 1.581 mmol, 3.0 eq). The reaction was degassed by bubblingargon through for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05eq) was added and the reaction sealed and heated in the microwave to140° C. for 45 minutes. The reaction was partitioned between EtOAc (80mL) and NaHCO₃ (80 mL). The organics were washed with brine (80 mL),dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10% MeOH[2M NH3]—CH₂Cl₂) yielded the title compound (0.255 g, %) as a yellowoil; ¹H nmr (400 MHz, CDCl₃) δ 7.88 (1H, s, triazoleH-3), 7.38-7.35 (6H,m, 6H of C(C₆H₅)₃), 7.21-7.11 (9H, m, 9H of C(C₆H₅)₃), 7.02 (1H, dd, J8.0, 2.0 Hz, oxobenzoxazapineH-8), 6.97 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.36 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.16 (2H, t, J 5.5 Hz, 2H ofNCH₂CH₂N), 3.82 (2H, s, ArCH₂N or NCH₂CN), 3.69 (2H, s, ArCH₂N orNCH₂CN), 3.51 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 2.91 (2H,t, J 5.5 Hz, 2H of ArCH₂CH₂N), 2.88 (3H, s, NCH₃); m/z: 593 [M+Na]⁺, 243[C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group

To a solution of the trityl protected amine (0.255 g, 0.447 mmol, 1.0eq) in dioxazne (4.0 mL) was added hydrogen chloride (0.56 mL of a 4Msolution in dioxane, 2.237 mmol, 5.0 eq). A white precipitate formed.The reaction was stirred at room temperature for 14 hours. The reactionwas concentrated to dryness and used without purification; m/z: 329[M+H]⁺.

Formation of(S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of the aminooxobenzoxazapine hydrochloride (0.377 mmol,1.0 eq) and benzyltriazole carboxylic acid (0.077 g, 0.377 mmol, 1.0 eq)in dimethylformamide (4.0 mL) was added diisopropylethylamine (0.122 g,0.16 mL, 0.943 mmol, 2.5 eq). The reaction was cooled to 0° C. and HATU(0.143 g, 0.377 mmol, 1.0 eq) added. The reaction was stirred at 0° C.for 2 hours and room temperature for 18 hours. The reaction waspartitioned between EtOAc—CH₂Cl₂ (9:1, 60 mL) and NaHCO₃-water (1:1, 60mL). The organics were washed with brine (60 mL). The combined aqueousphase was back-extracted with EtOAc (30 mL). The combined organics werewashed with water (90 mL) and brine (90 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. MPLC (0→8% MeOH—CH₂Cl₂) yielded thetitle compound as a white solid; ¹H nmr (400 MHz, CDCl₃) δ 7.90 (1H, brm, NH), 7.75 (1H, s, triazoleH-3), 7.29-7.21 (7H, m, 7×ArH), 7.16 (1H,d, J 8.0 Hz, oxobenzoxazapineH-9), 5.10 (1H, oxobenzoxazapineH-3), 4.74(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, t, 10.0Hz, 1H of oxobenzoxazapineH-2), 4.21 (2H, t, J 5.5 Hz, 2H of NCH₂CH₂N),4.15 (2H, s, NCH ₂C₆H5), 3.84, 3.78 (2H, 2d AB system, J 15.5 Hz, ArCH₂Nor NCH₂C), 3.77, 3.73 (2H, 2d AB system, J 13.5 Hz, ArCH₂N or NCH₂C),3.40 (3H, s, NCH₃), 3.02 (2H, t, J 5.5 Hz, 2H of NCH_(2C)H₂N); m/z: 514[M+H]⁺ (found [M+H]⁺, 514.2324, C₂₆H₂₇N₉O₃ requires [M+H]⁺ 514.2310).

Additional exemplary compound embodiments are described below.

(S)-5-benzyl-3-((7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide

¹H nmr (400 MHz, D₆DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H, d, J2.0 Hz, oxobenzoxazapineH-6), 7.25 (1H, dd, J 8.0, 2.0 Hz,oxobenzoxazapineH-8), 7.20-7.15 (5H, m, oxobenzoxazapineH-9, 4H ofC₆H₅), 7.09-7.04 (1H, m, 1H of C₆H₅), 5.47 (1H, br s, OH), 4.81-4.74(1H, m, oxobenzoxazapineH-3), 4.39-4.36 (2H, m, 2H ofoxobenzoxazapineH-2), 3.84 (2H, s, CH ₂C₆H₅), 3.28 (3H, s, NCH₃), 1.44(6H, s, C(CH ₃)₂OH); m/z: 442 [M+H]⁺.

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.76 (1H, dd, J 4.0, 1.5 Hz, quinolineH-2),8.03 (2H, m, NH, quinolineH-4), 8.01 (1H, d, J 9.5 Hz, quinolineH-8),7.99 (1H, s, triazoleH-5), 7.40 (1H, dd, J 9.0, 3.0 Hz, quinolineH-7),7.37-7.7.33 (4H, m, 4H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.28-7.24(3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 2.5 Hz,quinolineH-5), 7.10 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.36 (2H, s,NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.30 (2H, t, J 7.0Hz, CCH₂CH ₂O), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 2.98 (2H, t, J 7.0 Hz, CCH₂CH₂O); m/z: 573 [M+H]⁺ (found [M+H]⁺, 573.2244, C₃₃H₂₈N₆O₄ requires[M+H]⁺ 573.2245).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.73 (1H, dd, J 4.0, 1.5 Hz, quinolineH-2),8.05 (2H, m, NH, quinolineH-4), 8.00 (1H, d, J 9.5 Hz, quinolineH-8),7.40 (1H, dd, J 9.5, 3.0 Hz, quinolineH-7), 7.34 (1H, m, quinolineH-3),7.25 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.25-7.20 (6H, m,C₆H₅, oxobenzoxazapineH-7), 7.11 (1H, d, J 3.0 Hz, quinolineH-5), 7.09(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (2H, t, J 7.0 Hz, CCH₂CH ₂O), 4.26 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.37(3H, s, NCH₃), 2.98 (2H, t, J 7.0 Hz, CCH ₂CH₂O); ¹³C nmr (100 MHz,CDCl₃) δ 168.7, 156.6, 149.7, 148.0, 144.3, 136.0, 134.9, 131.0, 130.8,129.2, 128.8 (2C), 128.6, 127.1, 126.5, 123.1, 122.4, 121.4, 121.0,106.3, 86.6, 80.7, 77.2, 66.2, 49.1, 35.4, 33.4, 20.4; m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2262, C₃₃H₂₈N₆O₄ requires [M+H]⁺ 573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.38-7.33 (3H, m, 3H of C₆H₅), 7.27-7.24 (2H, m, 2H ofC₆H₅), 7.19 (2H, m, oxobenzoxazapineH-6, H-8), 7.15 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.35 (2H, s, NCH ₂C₆H₅), 5.09 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26-4.21 (3H, m, 1H of oxobenzoxazapineH-2, 2H ofNCH₂CH₂N), 3.87 (2H, s, 2H of ArCH₂NCH₂C), 3.75 (2H, s, 2H ofArCH₂NCH₂C), 3.40 (3H, s, NCH₃), 3.01 (2H, td, J 5.0, 1.5 Hz, 2H ofNCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.4, 156.6, 153.5 (q, J39.5 Hz), 152.2, 149.6, 143.9, 136.4, 134.5, 133.7, 129.2, 129.0, 128.2,127.8, 123.4, 123.3, 119.2 (q, J 270.5 Hz), 77.2, 60.6, 54.3, 50.7,49.2, 48.4, 47.1, 35.6; ¹⁹F nmr (380 MHz, CDCl₃) δ −65.4 m/z: 582 [M+H]⁺(found [M+H]⁺, 582.2188, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27-7.21 (6H, m,C₆H₅, oxobenzoxazapineH-8), 7.21 (1H, dd, J 7.5, 2.0 Hz,oxobenzoxazapineH-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.07(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.69 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.29-4.23 (3H, m, 1H ofoxobenzoxazapineH-2, 2H of NCH₂CH₂N), 4.12 (2H, s, CH ₂C₆H₅), 3.86 (2H,s, 2H of ArCH₂NCH₂C), 3.76 (2H, s, 2H of ArCH₂NCH₂C), 3.39 (3H, s,NCH₃), 3.03 (2H, t, J 5.5 Hz, 2H of NCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃)δ 168.8, 158.7, 153.4 (q, J 39.5 Hz), 152.2, 149.6, 136.3, 135.7, 134.6,128.8, 128.7, 127.9, 127.1, 123.4, 123.2, 123.1, 119.2 (q, J 269.5 Hz),77.1, 60.7, 50.4, 49.4, 48.6, 47.1, 35.6, 33.0; ¹⁹F nmr (380 MHz, CDCl₃)δ −65.3 m/z: 582 [M+H]⁺ (found [M+H]⁺, 582.2167, C₂₇H₂₆F₃N₉O₃ requires[M+H]⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, dd, J 4.5, 2.0 Hz, quinolineH-2),8.09-8.06 (2H, m, NH, quinolineH-4), 7.70 (1H, d, J 9.0 Hz,quinolineH-5), 7.50 (1H, d, J 2.5 Hz, quinolineH-8), 7.27-7.17 (9H, m,quinolineH-3, H-6, oxobenzoxazapineH-6, H-8, C₆H₅), 7.07 (1H, d, J 8.5Hz, oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (2H, td, J 7.0, 2.5 Hz, OCH ₂CH₂C), 4.24 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅),3.36 (3H, s, NCH₃), 2.97 (2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz,CDCl₃) δ 168.7, 159.6, 158.6, 150.3, 149.6, 149.5, 136.0 (2C), 135.9,131.0, 128.9, 128.8, 128.7, 127.0, 126.5, 123.7, 123.0, 121.0, 120.1,119.1, 107.9, 86.8, 80.6, 77.2, 66.1, 49.2, 35.5, 33.2, 20.3; m/z: 573[M+H]⁺ (found [M+H]⁺, 573.2269, C₃₃H₂₈N₆O₄ requires [M+H]⁺ 573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.20 (1H, dd, J 4.5, 2.0 Hz, quinolineH-2),8.06 (1H, dd, J 8.0, 1.5 Hz, quinolineH-4), 8.03 (1H, d, J 7.0 Hz, NH),7.99 (1H, s, triazoleH-5), 7.70 (1H, d, J 9.0 Hz, quinolineH-5), 7.45(1H, d, J 2.5 Hz, quinolineH-8), 7.37-7.33 (3H, m, 3H of C₆H₅,oxobenzoxazapineH-6), 7.27-7.22 (6H, m, quinolineH-6, H-3,oxobenzoxazapineH-8, 3H of C₆H₅, oxobenzoxazapineH-6), 7.09 (1H, dd, J8.0, 0.5 Hz, oxobenzoxazapineH-9), 5.35 (2H, s, NCH ₂C₆H₅), 5.06 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.33 (2H, t, J 7.0 Hz, OCH ₂CH₂C), 4.23 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 2.98(2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 159.4,158.4, 156.6, 150.6, 149.8, 149.7, 143.9, 135.9, 135.7, 133.7, 130.9,129.2, 128.9, 128.2, 126.5, 123.7, 123.1, 121.0, 119.9, 119.1, 108.2,86.6, 80.7, 77.1, 66.1, 54.3, 49.1, 38.6, 35.5, 20.3; m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2249, C₃₃H₂₈N₆O₄ requires [M+H]⁺ 573.2245).

(S)-5-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.27-7.20 (3H, m,oxobenzoxazapineH-6, H-8, 1H of C₆H₃F₂), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 6.82-6.74 (2H, m, 2H of C₆H₃F₂), 4.99 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₃F₂), 3.39 (3H, s, NCH₃), 1.61(6H, s, C(CH ₃)₂OH); ¹⁹F nmr (380 MHz, CDCl₃) δ −111.2; −113.2; m/z: 478[M+H—H₂O]⁺ (found [M+H]⁺, 496.1795, C₂₅H₂₃F₂N₅O₄ requires [M+H]⁺496.1791).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.89 (1H, dd, J 4.0, 2.0 Hz, quinolineH-2),8.63 (1H, ddd, J 8.5, 2.0, 1.0 Hz, quinolineH-4), 8.02 (1H, d, J 7.5 Hz,NH), 7.99 (1H, s, triazoleH-5), 7.70 (1H, d, J 8.5 Hz, quinolineH-8),7.59 (1H, dd, J 8.5, 7.5 Hz, quinolineH-7), 7.38-7.33 (4H, m,quinolineH-3, 3H of C₆H₅, oxobenzoxazapineH-6), 7.26-7.22 (4H, m,oxobenzoxazapineH-8, 3H of C₆H₅, oxobenzoxazapineH-6), 7.09 (1H, d, J8.0 Hz, oxobenzoxazapineH-9), 6.89 (1H, dd, J 7.5, 0.5 Hz,quinolineH-6), 5.35 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.73 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.35 (2H, t, J 7.0 Hz, OCH ₂CH₂C), 4.24 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.37 (3H, s, NCH₃), 3.03 (2H,t, J 7.0 Hz, OCH₂CH ₂C); m/z: 573 [M+H]⁺ (found [M+H]⁺, 573.2251,C₃₃H₂₈N₆O₄ requires [M+H]⁺ 573.2245).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, dd, J 4.0, 2.0 Hz, quinolineH-2),8.64 (1H, ddd, J 8.5, 2.0, 1.0 Hz, quinolineH-4), 8.07 (1H, d, J 7.5 Hz,NH), 7.69 (1H, d, J 8.5 Hz, quinolineH-8), 7.59 (1H, dd, J 8.5, 7.5 Hz,quinolineH-3), 7.26-7.17 (7H, m, C₆H₅, oxobenzoxazapineH-6, H-8), 7.08(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 6.90 (1H, dd, J 8.0, 0.5 Hz,quinolineH-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.36 (2H, t, J 7.0Hz, OCH ₂CH₂C), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.36 (3H, s, NCH₃), 3.04(2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.5,153.9, 150.6, 149.7, 148.9, 136.0, 131.0, 130.9, 129.4, 128.8, 128.7,127.0, 126.5, 123.1, 121.8, 121.0, 120.9, 120.3, 105.4, 86.7, 80.7,77.2, 49.1, 35.5, 33.2, 20.5; m/z: 573 [M+H]⁺ (found [M+H]⁺, 573.2266,C₃₃H₂₈N₆O₄ requires [M+H]⁺ 573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 8.02 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3×ArH), 7.29-7.7.26 (2H, m, 2×ArH), 7.20(2H, m, 2×ArH), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.38 (2H,s, NCH ₂C₆H₅), 5.12 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.26 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.15 (2H, t, J 5.5 Hz, 2H ofNCH₂CH₂N), 3.98, 3.93 (2H, 2d AB system, J 15.5 Hz, 2H of ArCH₂NCH₂),3.76 (2H, s, 2H of ArCH₂NCH₂), 3.42 (3H, s, NCH₃), 2.96 (2H, dt, J 4.0,5.5 Hz, 2H of NCH₂CH₂N); ¹⁹F nmr (380 MHz, CDCl₃) δ −63.2; m/z: 582[M+H]⁺ (found [M+H]⁺, 582.2173, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27-7.19 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.16 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.09 (1H, dt, J 10.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 10.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (4H, m, 2H of NCH₂CH₂N), 2H of ArCH₂NCH₂ orCH ₂C₆H₅), 3.93 (2H, s, 2H of ArCH₂NCH₂ or CH ₂C₆H₅), 3.78, 3.74 (2H, 2dAB system, J 13.5 Hz, 2H of ArCH₂NCH₂), 3.40 (3H, s, NCH₃), 2.97 (2H, t,J 5.5 Hz, 2H of NCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.6,152.0, 149.6, 143.4 (q, J 40.0 Hz), 136.4, 135.8, 134.3, 128.8, 128.7,127.9, 127.1, 126.9, 123.4, 123.2, 118.3 (q, J 270.5 Hz), 77.2, 60.8,49.5, 49.4, 43.6, 35.6, 33.1; ¹⁹F nmr (380 MHz, CDCl₃) δ −63.2; m/z: 582[M+H]⁺ (found [M+H]⁺, 582.2208, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺ 582.2183).

(S)-1-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s,triazoleH-5), 7.40-7.36 (3H, m, 3H of C₆H₅), 7.29-7.23 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.38 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); m/z:458 [M+H]⁺ (found [M+H]⁺, 458.2205, C₂₆H₂₇N₅O₃ requires [M+H]⁺458.2187).

(S)-5-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.07 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J Hz, 1H of oxobenzoxazapineH-2),4.15 (2H, s, CH ₂C₆H₅), 3.40 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹³Cnmr (100 MHz, CDCl₃) δ 168.7, 158.5, 149.2, 135.9, 135.8, 130.9, 128.8,128.7, 127.0, 126.4, 122.8, 121.8, 99.4, 77.6, 77.2, 49.1, 35.5, 33.2,30.9, 27.9; m/z: 458 [M+H]⁺ (found [M+H]⁺, 458.2200, C₂₆H₂₇N₅O₃ requires[M+H]⁺ 458.2187).

(S)-1-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s,triazoleH-5), 7.38-7.34 (3H, m, 3H of C₆H₅), 7.29-7.25 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.36 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 2.55-2.49 (2H, m, 2H ofcBuH-2, H-4), 2.33 (2H, m, 2H of cBuH-2, H-4), 1.87 (2H, m, cBuH-3);m/z: 472 [M+H]⁺, 454 [M+H—H₂O]⁺ (found [M+H]⁺, 472.1994, C₂₆H₂₅N₅O₄requires [M+H]⁺ 472.1979).

(S)-5-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J 7.5 Hz, NH), 7.29-7.20 (7H, m,C₆H₅, 2H of oxobenzoxazapineH-6, H-8, H-9), 7.10 (1H, dd, J 7.5, 1.0 Hz,1H of oxobenzoxazapineH-6, H-8, H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15, 4.11 (2H, 2d AB system, J 16.0 Hz, CH₂C₆H₅), 3.39 (3H, s, NCH₃), 2.57-2.50 (2H, m, 2H of cBuH-2, H-4), 2.35(2H, m, 2H of cBuH-2, H-4), 1.92-1.84 (2H, m, cBuH-3); ¹³C (100 MHz,CDCl₃) δ 168.7, 158.7, 149.9, 136.0, 135.8, 131.0, 128.8, 128.7, 127.0,126.5, 123.0, 120.4, 93.4, 81.9, 76.9, 68.2, 49.1, 38.5, 35.5, 33.0,13.0; m/z: 454 [M+H—H₂O]⁺ (found [M+H]⁺, 472.1999, C₂₆H₂₅N₅O₄ requires[M+H]⁺ 472.1979).

(S)-1-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.99 (1H, s,triazoleH-5), 7.38-7.34 (3H, m, 3H of C₆H₅), 7.28-7.26 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.36 (2H, s, NCH₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 2.08-1.99 (4H, m, cPentaneH-2,H-5), 1.90-1.84 (2H, m, 2H of cPentaneH-3, H-4), 1.83-1.76 (2H, m, 2H ofcPentaneH-3, H-4); m/z: 486 [M+H]⁺, 468 [M+H—H₂O]⁺ (found [M+H]⁺,486.2122, C₂₇H₂₇N₅O₄ requires [M+H]⁺ 486.2136).

(S)-5-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-7), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃),2.08-1.97 (4H, m, cPentaneH-2, H-5), 1.90-1.85 (2H, m, 2H ofcPentaneH-3, H-4), 1.82-1.76 (2H, m, 2H of cPentaneH-3, H-4); m/z: 468[M+H—H₂O]⁺ (found [M+H]⁺, 486.2154, C₂₇H₂₇N₅O₄ requires [M+H]⁺486.2136).

(S)-1-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.02 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3H of C₆H₅), 7.31-7.27 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.14 (1H, dd, J 8.0, 1.0 Hz,oxobenzoxazapineH-9), 5.37 (2H, s, NCH ₂C₆H₅), 5.08 (1H, dt, J 11.5, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.95 (2H, dt, J 12.0, 4.5 Hz, 2H of pyranH-2,H-6), 3.72 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H of pyranH-2, H-6), 3.42(3H, s, NCH₃), 2.07-2.02 (2H, m, 2H of pyranH-3, H-5), 1.89 (2H, ddd, J13.0, 9.0, 4.0 Hz, 2H of pyranH-3, H-5); m/z: 502 [M+H]⁺, 484 [M+H—H₂O]⁺(found [M+H]⁺, 502.2105, C₂₇H₂₇N₅O₅ requires [M+H]⁺ 502.2085).

(S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28-7.19 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.64 (1H, dd, J 9.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH₂C₆H₅), 3.93 (2H, dt, J 12.0, 4.5Hz, 2H of pyranH-2, H-6), 3.70 (2H, ddd, J 11.5, 9.0, 2.5 Hz, 2H ofpyranH-2, H-6), 3.37 (3H, s, NCH₃), 2.03 (2H, m, 2H of pyranH-3, H-5),1.88 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H of pyranH-3, H-5); ¹³C nmr (100MHz, CDCl₃) δ 168.6, 158.7, 150.1, 136.1, 135.7, 131.1, 128.9, 128.8,127.1, 126.6, 123.2, 120.0, 92.3, 83.4, 77.3, 66.1, 64.8, 49.1, 39.9,35.6, 33.1; m/z: 484 [M+H—H₂O]⁺ (found [M+H]⁺, 502.2080, C₂₇H₂₇N₅O₅requires [M+H]⁺ 502.2085).

(S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.40 (2H, m, 2H of C₆H₅),7.27-7.22 (3H, m, oxobenzoxazapineH-6, H-8, 1H of C₆H₅), 7.10 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 7.05 (2H, m, 2H of C₆H₅), 6.93 (1H, dd, J5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 1.61 (6H,s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7,151.3, 150.1, 150.0, 136.2, 130.8, 130.3, 126.4, 125.6, 123.0, 120.7,120.3, 114.4, 110.6, 94.4, 80.7, 77.2, 65.6, 49.3, 35.4, 31.4; m/z: 472[M+H]+(found [M+H]⁺, 472.1891, C₂₇H₂₅N₃O₅ requires [M+H]⁺ 472.1867).

(S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.14 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4),4.80 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.70 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.16 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 2.98(1H, br s, OH); m/z: 474 [M+H]⁺ (found [M+H]⁺, 474.1789, C₂₅H₂₃N₅O₅requires [M+H]⁺ 474.1772).

(S)-1-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s,triazoleH-5), 7.37 (3H, m, 3H of C₆H₅), 7.28-7.25 (4H, m, 2H of C₆H₅,oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9),5.35 (2H, s, NCH ₂C₆H₅), 5.04 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.89 (2H, dd, J 7.0, 1.0 Hz, 2H of oxetaneH-2,H-4), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H of oxobenzoxazapineH-2,H-4), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.26(1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.53 (1H, s, OH),3.38 (3H, s, NCH₃); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.4, 156.5,150.4, 144.0, 136.1, 133.7, 130.9, 129.2, 129.0, 128.2, 126.6, 123.4,119.5, 88.9, 84.5, 77.1, 67.3, 54.4, 53.4, 49.1, 35.5; m/z: 474 [M+H]⁺.

(S)-5-benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0Hz, 2H of C₆H₅), 7.20-7.15 (5H, m, 3H of C₆H₅, oxobenzoxazapineH-6,H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.41 (1H, q, J 1.0Hz, 1H of ═CH₂), 5.32 (1H, m, 1H of ═CH₂), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₅), 3.38 (3H, s, NCH₃), 1.98(3H, t, J Hz, C(CH ₃)═CH₂); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.7,154.6, 149.8, 136.0, 135.9, 130.9, 128.8, 128.7, 127.0, 126.4 (2C),123.1, 122.6, 121.0, 91.3, 86.7, 77.2, 49.2, 35.5, 33.0, 23.3; m/z: 464[M+Na]⁺, 442 [M+H]⁺ (found [M+H]⁺, 442.1869, C₂₅H₂₃N₅O₃ requires [M+H]⁺442.1874).

(S)-5-benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.29-7.19 (5H, m,C₆H₅), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 7.03 (1H, d, J 2.0Hz, oxobenzoxazapineH-6), 7.00 (1H, m, oxobenzoxazapineH-8), 5.04 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.22 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃), 2.60(2H, m, CH ₂CH₂CH(CH₃)₂), 1.60 (1H, m, CH₂CH₂CH(CH₃)₂), 1.52-1.46 (2H,m, CH₂CH ₂CH(CH₃)₂), 0.94 (6H, d, J 6.5 Hz, CH₂CH₂CH(CH ₃)₂); m/z: 448[M+H]⁺ (found [M+H]⁺, 448.2335, C₂₅H₂₉N₅O₃ requires [M+H]⁺ 448.2343).

(S)-5-benzyl-N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.25 (2H, m,2H of C₆H₅), 7.19 (5H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.09(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.63 (1H, dd, J 9.0, 8.0 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 10.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃ orOCH₃), 3.39 (3H, s, NCH₃ or OCH₃), 1.54 (6H, s, C(CH)₂OCH₃); m/z: 474[M+H]⁺, 442 [M+H—CH₃OH]⁺ (found [M+H]⁺, 474.2138, C₂₆H₂₇N₅O₄ requires[M+H]⁺ 474.2136).

(S)-1-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.39-7.34 (3H, m, 3H of C₆H₅), 7.27-7.23 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-8, H-9), 7.12 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 5.36 (2H, s, NCH ₂C₆H₅), 5.05 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂OH); m/z:460 [M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1968, C₂₅H₂₅N₅O₄ requires[M+H]⁺ 460.1979).

(S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.18 (7H, m,C₆H₅, oxobenzoxazapineH-7, H-9), 7.11 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14, 4.10 (2H, 2d, J 16.0 Hz, CH ₂C₆H₅), 3.37(3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ168.7, 158.7, 149.5, 136.1, 135.9, 129.0, 128.8, 128.7, 127.0, 126.0,123.1, 122.2, 95.1, 80.6, 76.9, 65.5, 49.2, 35.4, 33.0, 31.4 (2C); m/z:442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1972, C₂₅H₂₅N₅O₄ requires [M+H]⁺460.1979).

(S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.83 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyridineH-3), 7.60 (1H, d, J 2.5 Hz, pyridineH-6), 7.42-7.38 (2H, m,2H of C₆H₅), 7.28-7.22 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-7, H-9),7.13 (1H, d, J 8.0 Hz, oxobenzoxazapineH-6), 7.07-7.04 (2H, m, 2H ofC₆H₅), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyridineH-4), 5.01 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.6,136.4, 130.3, 128.9, 126.0, 125.7, 123.0, 122.0, 120.7, 114.4, 110.6,94.9, 80.6, 77.2, 65.6, 49.4, 35.3, 31.4; m/z: 472 [M+H]⁺ (found [M+H]⁺,472.1873, C₂₇H₂₅N₃O₅ requires [M+H]⁺ 472.1867).

(S)-5-(2,6-dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.33-7.29 (3H, m,3H of C₆H₃Cl₂, oxobenzoxazapineH-6), 7.226-7.24 (1H, m, 1H of C₆H₃Cl₂,oxobenzoxazapineH-6), 7.18-7.15 (1H, m, oxobenzoxazapineH-8)), 7.10 (1H,d, J 8.5 Hz, oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.48 (2H, s, CH ₂C₆H₃Cl₂), 4.27 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 1.61 (6H, s,C(CH₃)₂); m/z: 532, 530, 528 [M+H]⁺ 514, 512, 510 [M+H—H₂O]⁺ (found[M+H]⁺, 528.1201, C₂₅H₂₃Cl₂N₅O₄ requires [M+H]⁺ 528.1200).

(S)-5-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30-7.17 (8H, m,C₆H₅, oxobenzoxazapineH-6, H-7, H-9), 5.08 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30-4.25 (3H, m, 1H of oxobenzoxazapineH-2,NCH₂CH₂N), 4.14 (2H, s, CH₂C₆H₅), 3.88, 3.83 (2H, 2d AB system, J 16.0Hz, 2H of ArCH₂NCH₂), 3.76 (2H, s, ArCH₂NCH₂), 3.40 (3H, s, NCH₃),3.09-3.02 (2H, m, NCH₂CH₂N); ¹⁹F nmr (380 MHz, CDCl₃) δ −65.3; m/z: 604[M+Na]⁺582 [M+H]⁺.

(S)-1-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-7,H-9), 7.28-7.25 (2H, m, 2H of C₆H₅, oxobenzoxazapineH-6, H-7, H-9),7.23-7.17 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-7, H-9), 5.37 (2H,s, NCH ₂C₆H₅), 5.11 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28-4.23 (3H, m, 1Hof oxobenzoxazapineH-2, 2H of NCH₂CH₂N), 3.90, 3.86 (2H, 2d AB system, J16.0 Hz, 2H of ArCH₂NCH₂), 3.79, 3.75 (2H, 2d AB system, J 13.5 Hz, 2Hof ArCH₂NCH₂), 3.42 (3H, s, NCH₃), 3.10-3.02 (2H, m, 2H of NCH₂CH₂N);¹⁹F nmr (380 MHz, CDCl₃) δ −65.4; m/z: 604 [M+Na]⁺, 582 [M+H]⁺.

(S)—N-(7-(3-hydroxy-3-(methyl-d₃)but-1-yn-1-yl-4,4,4-d₃)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-3), 7.60 (1H, d, J 2.5 Hz, pyH-4), 7.42-7.38 (2H, m, 2H ofC₆H₅), 7.27-7.22 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.10-7.05 (2H, m, 2H of C₆H₅,oxobenzoxazapineH-6, H-8), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-6), 5.01(1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃); m/z: 478 [M+H]⁺, 460[M+H—H₂O]⁺ (found [M+H]⁺, 478.2255, C₂₇H₁₉D₆N₃O₄ requires [M+H]⁺478.2244).

(S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d₃)but-1-yn-1-yl-4,4,4-d₃)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃); ¹³Cnmr (100 MHz, CDCl₃) δ 168.6, 158.5, 149.9, 136.0, 135.8, 131.0, 128.8(2C), 127.1 (2C), 126.5, 123.1, 120.5, 94.6, 80.6, 77.2, 65.3, 49.1,35.5, 33.2, 30.5 (m); m/z: 466 [M+H]⁺, 448 [M+H—H₂O]⁺ (found [M+H]⁺,466.2356, C₂₅H₁₉D₆N₅O₄ requires [M+H]⁺ 466.2356).

(R)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[α]₅₈₂ ^(20.2)+135.9 (CHCl₃, c 0.54); ¹H nmr (400 MHz, CDCl₃) δ 8.08(1H, d, J 7.5 Hz, NH), 7.30-7.23 (7H, m, C₆H₅, oxobenzoxazapineH-6,H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₅), 3.40 (3H, s, NCH₃), 1.63(6H, s, C(CH₃)₂OH); m/z: 460 [M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺,460.1985, C₂₅H₂₅N₅O₄ requires [M+H]⁺ 460.1979).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.99 (1H, d, J 6.5 Hz, NH), 7.36-7.29 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.13 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 4.97 (1H, ddd, J 11.0, 7.5, 7.0 Hz,oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, m, 1H of oxobenzoxazapineH-2), 4.26 (2H,s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃), 1.63 (6H, s, C(CH₃)₂); m/z: 484[M+Na]⁺, 443 [M+H—H₂O]⁺ (found [M+H]⁺, 443.1727, C₂₅H₂₄N₄O₅ requires[M+H—H₂O]⁺ 443.1714).

(S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.42-7.39 (2H, m, 2H ofC₆H₅), 7.31 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-7), 7.27-7.22 (2H,m, 1H of C₆H₅, oxobenzoxazapineH-9), 7.17 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 7.07-7.05 (2H, m, 2H of C₆H₅), 6.93 (1H, dd, J5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.93 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, d, J 7.0 Hz, 2Hof oxetaneH-2, H-4), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); m/z: 486 [M+H]⁺, (found[M+H]⁺, 486.1674, C₂₃H₂₃N₃O₆ requires [M+H]⁺ 486.1660).

(S)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.97 (1H, s, OH),7.32-7.22 (6H, m, C₆H₅, oxobenzoxazapineH-7), 7.20 (1H, d, J 2.0 Hz,oxobenzoxazapineH-9), 7.14 (1H, d, J 8.5 Hz, 1H of oxobenzoxazapineH-6),4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.92 (2H, d, J 7.0Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, d, J 6.5 Hz, 2H of oxetaneH-2,H-4), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.25 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅),3.40 (3H, s, NCH₃); m/z: 474 [M+H]⁺, 456 [M+H—H₂O]⁺ (found [M+H]⁺,474.1784, C₂₅H₂₃N₅O₅ requires [M+H]⁺ 474.1772).

(3S,3aR,6R,6aS)-6-(((S)-3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-ylbenzoate

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 8.03 (2H, m, 2H ofCOC₆H₅), 7.59 (1H, tt, J 7.5, 1.0 Hz, 1H of COC₆H₅), 7.45 (2H, t, J 7.5Hz, 2H of COC₆H₅), 7.32-7.23 (7H, m, CH₂C₆ H ₅, oxobenzoxazapineH-6,H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 5.23 (1H, d, J 3.0Hz, isosorbateH-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.87, 4.83 (2H, 2d AB system, J 4.5 Hz, isosorbateH-3a, H-6a), 4.69 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.25-4.20 (2H, m, isosorbateH-5),4.15 (2H, s, CH ₂C₆H₅), 4.04, 3.95 (2H, 2d AB system, J 9.5 Hz,isosorbateH-2), 3.40 (3H, s, NCH₃); m/z: 650 [M+H]⁺ (found [M+H]⁺,650.2283, C₃₅H₃₁N₅O₈ requires [M+H]⁺ 650.2245).

5-benzyl-N—((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-b]furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.36 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.33-7.23 (5H, m,C₆H₅), 7.19 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.01 (1H, dd, J11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.65, 4.54 (2H, 2d AB system, J 4.5Hz, isosorbateH-3a, H-6a), 4.60 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, d, J 2.5 Hz, isosorbateH-6), 4.15 (2H,s, CH ₂C₆H₅), 3.99-3.91 (2H, m, 2H of isosorbateH-5), 3.93, 3.71 (2H, 2dAB system, J 8.5 Hz, isosorbateH-2), 3.40 (3H, s, NCH₃); ¹³C nmr (100MHz, CD₃OD) δ 169.1, 150.3, 136.5, 130.7, 128.4, 128.3, 126.8, 126.6,122.7, 119.9, 110.0, 89.5, 88.6, 87.1, 83.7, 78.1, 77.8, 77.5, 74.4,49.1, 34.4, 33.2; m/z: 546 [M+H]⁺ (found [M+H]⁺, 546.2007, C₂₈H₂₇N₅O₇requires [M+H]⁺ 546.1983).

methyl(S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.16 (2H, s, CH₂C₆H₅), 3.78 (3H, s, OCH₃), 3.41(3H, s, NCH₃), 1.58 (6H, s, C(CH₃)₂); m/z: 502 [M+H]⁺ (found [M+H]⁺,502.2107, C₂₇H₂₇N₅O₄ requires [M+H]⁺ 502.2085).

(S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.79 (1H, d, J 7.0 Hz, NH), 7.38-7.32 (4H, m,4H or C₆H₅, pyrazoleH-4 or H-5, oxobenzoxazapineH-6, H-8), 7.28-7.21(4H, m, 4H of C₆H₅, pyrazoleH-4 or H-5, oxobenzoxazapineH-6 or H-8),7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 6.74 (1H, d, J 2.5 Hz,pyrazoleH-4 or H-5), 5.31 (2H, s, NCH ₂C₆H₅), 5.05 (1H, dt, J 11.0, 7.0Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); m/z:459 [M+H]⁺, 441 [M+H—H₂O]⁺ (found [M+H]⁺, 459.2040, C₂₆H₂₆N₄O₄ requires[M+H]⁺ 459.2027).

(S)-5-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m,oxobenzoxazapineH-6, H-8), 7.21 (1H, m, 1H of C₆H₄F), 7.10 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 7.01 (1H, br d, J 8.0 Hz, 1H of C₆H₄F), 6.96(1H, br d, J 9.5 Hz, 1H of C₆H₄F), 6.90 (1H, td, J 8.5, 2.5 Hz, 1H ofC₆H₄F), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H,dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₄F), 3.40 (3H,s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CD₃OD) δ 168.5,164.0, 161.6, 149.9, 138.5, 135.9, 131.0, 130.2 (d, J 8.5 Hz), 128.8,126.5, 124.5 (d, J 2.5 Hz), 123.0, 120.5, 115.8 (d, J 22.0 Hz), 113.9(d, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4; ¹⁹F nmr(380 MHz, CDCl₃) δ −112.6; m/z: 460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1901,C₂₅H₂₄FN₅O₄ requires [M+H]⁺ 478.1885).

(S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27-7.25 (2H, m,oxobenzoxazapineH-6, H-8), 7.17 (2H, dd, J 8.5, 5.5 Hz, 2H of C₆H₄F),7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 6.90 (2H, t, J 8.5 Hz, 2Hof C₆H₄F), 4.99 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.64 (1H,dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.29 (1H, dd, J 11.5,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.09 (2H, s, CH ₂C₆H₄F), 3.39 (3H,s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹⁹F nmr (380 MHz, CDCl₃) δ −115.6;m/z: 478 [M+H]⁺ 460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1902, C₂₅H₂₄FN₅O₄requires [M+H]⁺ 478.1885).

(S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.16 (3H, m,oxobenzoxazapineH-6, H-8, 1H of C₆H₄F), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.01 (1H, td, J 7.5, 1.0 Hz, 1H of C₆H₄F),7.00-6.96 (1H, m, 1H of C₆H₄F), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₄F), 3.38 (3H, s, NCH₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 160.7 (d, J 246.3Hz), 158.5, 149.9, 136.0, 131.0 (d, J 4.0 Hz), 131.0, 129.1, 129.0 (d, J8.5 Hz), 126.5, 126.3, 124.4 (d, J 4.0 Hz), 123.1, 120.4, 115.4 (d, J12.0 Hz), 94.6, 80.6, 76.9, 65.6, 49.1, 35.5, 31.4, 26.3; ¹⁹F nmr (380MHz, CDCl₃) δ −117.5; m/z: 460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1895,C₂₅H₂₄FN₅O₄ requires [M+H]⁺ 478.1885).

(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.40-7.38 (6H, m, 3×2H of C₆H₅), 7.24-7.20(6H, m, 3×2H of C₆H₅), 7.18-7.12 (4H, m, 3×1H of C₆H₅, 1H ofoxbenzoxazapineH-6, H-8, H-9), 6.97-6.95 (2H, m, 2H ofoxobenzoxazapineH-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.55 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.28 (1H, d, J 8.5 Hz, NH), 2.88 (3H, s, NCH₃),1.63 (6H, s, C(CH ₃)₂OH); m/z: 561 [M−H+HCO₂H]⁻.

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33-7.31 (2H, m,oxobenzoxazapineH-8, H-9), 7.25-7.20 (5H, m, C₆H₅), 7.09 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₅), 3.40 (3H, s, NCH₃), 0.26(9H, s, Si(CH₃)₃); m/z: 474 [M+H]⁺ (found [M+H]⁺, 474.1981, C₂₅H₂₇N₅O₃Sirequires [M+H]⁺ 474.1956).

(S)-5-benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz,oxobenzoxazapineH-8), 7.35-7.26 (6H, m, C₆H₅, oxobenzoxazapineH-6), 7.14(1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 5.04 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₅), 3.42 (3H, s, NCH₃), 3.12(1H, s, HCC); ¹³C nmr (100 MHz, CDCl₃) δ 168.6, 150.4, 136.1, 131.5,128.9 (2C), 127.3, 127.0, 123.3, 119.8, 82.0, 78.1, 77.2, 49.1, 35.5,33.5; m/z: 402 [M+H]⁺ (found [M+H]⁺, 402.1561, C₂₂H₁₉N₅O₃ requires[M+H]⁺ 402.1576).

(S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.24 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.06 (1H, d, J 8.0Hz, oxobenzoxazapineH-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.72 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3); m/z: 275 [M+H]⁺ (found [M+H]⁺, 275.1390,C₁₅H₁₈N₂O₃ requires [M+H]⁺ 275.1404).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 7.83 (1H, s,triazoleH-5), 7.32-7.21 (5H, m, 5H of C₆H₄, oxobenzoxazapineH-6), 7.16(1H, dd, J 9.0, 2.0 Hz, oxobenzoxazapineH-8), 7.12 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.37 (2H, s, NCH ₂C₆H₄CH₃), 5.07 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 2.27 (3H, s, C₆H₄CH ₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.4, 156.5,149.9, 143.8, 136.8, 136.0, 131.4, 131.1, 130.9, 129.7, 129.4, 126.8,126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 52.6, 49.1, 35.5, 31.4,19.0; m/z: 474 [M+H]⁺, 456 [M+H—H₂O]⁺

(S)-1-([1,1′-biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, s, traizoleH-5), 8.06 (1H, d, J 7.0Hz, NH), 7.60-7.55 (4H, m, 4H of C₆H₄C₆H₅), 7.45-7.42 (2H, m, 2H ofC₆H₄C₆H₅), 7.38-7.34 (3H, m, 3H of C₆H₄C₆H₅), 7.28-7.26 (2H, m,oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),5.41 (2H, s, NCH ₂C₆H₄Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 169.1, 158.7, 157.0, 150.3, 144.3, 142.3, 140.4,136.3, 132.9, 131.2, 129.2, 129.0, 128.2, 128.0, 127.4, 126.8, 123.5,120.7, 94.9, 80.9, 77.5, 65.9, 54.4, 49.4, 35.8, 31.7; m/z: 536 [M+H]⁺,518 [M+H—H₂O]⁺

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.59 (1H, s,triazoleH-5), 7.28-7.21 (3H, m, 3H of oxobenzoxazapineH-6, H-8, H-9, C₆H ₃(CH₃)₂), 7.13-7.10 (3H, m, 3H of oxobenzoxazapineH-6, H-8, H-9,C₆H₃(CH ₃)₂), 5.41 (2H, s, NCH ₂C₆H₃(CH₃)₂), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 2.30 (6H, s, C₆H₃(CH ₃)₂),1.62 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.5,156.5, 149.9, 143.1, 138.1, 136.0, 130.9, 129.6, 129.0 (2C), 126.5,123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 49.1, 49.0, 35.5, 31.4, 19.6; m/z:488 [M+H]⁺, 470 [M+H—H₂O]⁺ (found [M+H]⁺, 488.2292, C₂₇H₂₉N₅O₄ requires[M+H]⁺ 488.2292).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, s, triazoleH-5), 8.03 (1H, d, J 7.0Hz, NH), 7.29-7.26 (2H, m, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz,oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.98 (2H, d, J 7.0 Hz, NCH ₂CH(CH₃)₂), 3.41 (3H,s, NCH₃), 2.30-2.23 (1H, m, CH(CH₃)₂), 1.62 (6H, s, C(CH ₃)₂OH), 0.91(6H, dd, J 6.5, 1.0 Hz, CH(CH ₃)₂); ¹³C nmr (100 MHz, CDCl₃) δ 168.9,158.5, 156.5, 149.9, 144.3, 136.0, 130.9, 126.5, 123.2, 120.4, 94.5,80.6, 77.1, 65.5, 57.6, 49.1, 35.5, 31.4, 29.0, 19.7; m/z: 426 [M+H]⁺,408 [M+H—H₂O]⁺ (found [M+H]⁺, 426.2126, C₂₂H₂₇N₅O₄ requires [M+H]⁺426.2136).

(S)-5-benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.30-7.18 (5H, m, 5H of C₆H₅,oxobenzoxazapineH-6, H-8, H-9), 7.13-7.06 (3H, m, 3H of C₆H₅,oxobenzoxazapineH-6, H-8, H-9), 6.85-6.77 (0.66H, m,oxobenzoxazapineH-3major), 5.34-5.27 (0.33H, m,oxobenzoxazapineH-3minor), 4.94 (0.33H, dd, J 12.0, 10.5 Hz,oxobenzoxazapineH-3minor), 4.84 (0.66H, dd, J 12.0, 9.5 Hz,oxobenzoxazapineH-3major), 4.55 (0.66H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2major), 4.50 (0.33H, m, 1H ofoxobenzoxazapineH-2minor), 4.11 (0.66H, s, CH ₂C₆H₅minor), 4.05 (1.32H,q, J 7.0 Hz, NCH ₂CH₃major), 3.91, 3.84 (1.32H, 2d AB system, J 15.5 Hz,CH ₂C₆H₅major), 3.50 (0.66H, q, J 7.0 Hz, NCH ₂CH₃minor), 3.28 (1H, s,NCH₃minor), 3.25 (2H, s, NCH₃major), 1.61 (2H, s, C(CH₃)₂OHminor), 1.57(4H, s, C(CH₃)₂OHmajor), 1.20 (3H, t, J 7.0 Hz, NCH₂CH ₃); m/z: 488[M+H]⁺, 470 [M+H—H₂O]⁺ (found [M+H]⁺, 488.2291, C₂₇H₂₉N₅O₄ requires[M+H]⁺ 488.2292).

(S)-5-benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m,oxobenzoxazapineH-6), 7.31 (1H, dd, J 8.0, 2.5 Hz, oxobenzoxazapineH-8),7.15 (5H, br s, C₆H₅), 7.02 (1H, dd, J 8.0, 1.0 Hz,oxobenzoxazapineH-9), 4.10 (2H, s, CH ₂C₆H₅), 3.36 (3H, s, NCH₃); ¹³C(100 MHz, 100 MHz) δ 168.7, 158.9, 149.1, 137.4, 135.8, 130.6, 128.8,128.7, 127.1, 126.4, 118.1, 77.2, 49.2, 35.5, 32.9; m/z: 458, 456 [M+H]⁺(found [M+H]⁺, 458.0651, C₂₀H₁₈BrN₅O₃ requires [M+H]⁺ 458.0645).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.72 (1H, d, J 7.0 Hz, NH), 7.36-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 6.30 (1H, br s, isoxazoleH-5), 4.99 (1H, dt, J11.0, 7.0 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.10 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 174.1, 168.4, 158.5,157.9, 149.9, 136.0, 135.2, 130.9, 128.9, 128.7, 127.4, 126.5, 123.1,120.4, 101.6, 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 33.2, 31.4; m/z: 460[M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1884, C₂₆H₂₅N₃O₅ requires[M+H]⁺ 460.1867).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.71 (1H, dd, J 5.5, 3.0 Hz, 1×ArH), 7.20 (1H,dd, J 5.5, 3.0 Hz, 1×ArH), 7.59 (1H, d, J 2.0 Hz, 1×ArH), 7.44 (1H, td,J 8.5, 2.0 Hz, 1×ArH), 7.41 (1H, br s, 1×ArH), 7.33-7.23 (6H, m, 6×ArH),5.03 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.60 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazapineH-2), 4.45 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.35 (2H, s, isoquinolineH-1), 4.16 (2H, sCH2C6H5), 3.50 (2H, t, J 6.5 Hz, isoquinolineH-3 or H-4), 3.42 (3H, s,NCH₃), 3.13 (2H, dd, J 7.0, 6.0 Hz, isoquinolineH-3 or H-4); m/z: 533[M+H]⁺ (found [M+H]⁺, 533.2296, C₃₁H₂₈N₆O₃ requires [M+H]⁺ 533.2296).

(S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26-7.19 (4H, m,oxobenzoxazapineH-6, H-7, 2H of C₆H₄F), 7.08 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.06-7.02 (1H, m, 1H of C₆H₄F), 7.03-6.99 (1H, m,1H of C₆H₄F), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.25 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.19 (2H, s, CH ₂C₆H₄F), 3.40(3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹³C nmr (100 MHz, CDCl₃) δ 168.8,160.7 (d, J 245.5 Hz), 158.5, 149.2, 135.8, 131.0 (d, J 4.0 Hz), 130.9,128.9 (d, J 8.5 Hz), 126.4, 124.3 (d, J 4.0 Hz), 123.1 (d, J 15.0 Hz),122.8, 121.8, 115.3 (d, J 21.5 Hz), 99.4, 77.6, 77.0, 49.2, 35.5, 30.9,27.9, 26.3; m/z: 476 [M+H]⁺ (found [M+H]⁺, 476.2100, C₂₅H₂₆FN₅O₃requires [M+H]⁺ 476.2092).

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.59 (1H, s,triazoleH-5), 7.26-7.22 (3H, m, oxobenzoxazapineH-6, H-8,C₆H₃(CH₃)₂H-4), 7.12 (2H, d, J 7.5 Hz, C₆H₃(CH₃)₂H-3, H-5), 7.09 (1H, d,J 9.0 Hz, oxobenzoxazapineH-9), 5.42 (2H, s, NCH ₂C₆H₃(CH₃)₂), 5.06 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 2.31 (6H, s, C₆H₃(CH₃)₂, 1.32(9H, s, C(CH₃)₃); m/z: 486 [M+H]⁺ (found [M+H]⁺, 486.2506, C₂₈H₃₁N₅O₃requires [M+H]⁺ 486.2500).

(S)-5-benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 4.99 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.21-4.11 (1H, m, 1H of NCH ₂CH₃), 4.16 (2H, s,NCH ₂C₆H₅), 3.66 (1H, heptet, J 7.0 Hz, 1H of NCH ₂CH₃), 1.63 (6H, s,C(CH ₃)₂OH), 1.19 (3H, t, J 7.0 Hz, NCH₂CH ₃); m/z: 456 [M+H—H₂O]⁺(found [M+H]⁺, 474.2143, C₂₆H₂₇N₅O₄ requires [M+H]⁺ 474.2136).

(S)—N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.30-7.28 (2H, m,oxobenzoxazapineH-6, H-8), 7.26-7.21 (1H, m, 1H of C₆H₄F), 7.12 (1H, d,J 8.5 Hz, oxobenzoxazapineH-9), 7.03 (1H, br d, J 7.5 Hz, 1H of C₆H₄F),6.98 (1H, br d, J 9.5 Hz, 1H of C₆H₄F), 6.92 (1H, td, J 8.5, 2.5 Hz, 1Hof C₆H₄F), 4.97 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.65 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0,10.5 Hz, 1H of oxobenzoxazapineH-2), 4.22-4.10 (1H, m, 1H of NCH ₂CH₃),4.14 (2H, s, CH ₂C₆H₄F), 3.66 (1H, heptet, J 7.0 Hz, 1H of NCH ₂CH₃),1.63 (6H, s, C(CH ₃)₂OH), 1.19 (3H, t, J 7.0 Hz, NCH₂CH ₃); ¹⁹F nmr (380MHz, CDCl₃) δ −112.6; m/z: 474 [M+H—H₂O]⁺ (found [M+H]⁺, 492.2047,C₂₆H₂₆FN₅O₄ requires [M+H]⁺ 492.2042).

(S)-5-benzyl-N-(7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.0 Hz, 1×NH), 7.54 (1H, s,1×NH), 7.35-7.24 (6H, m, C₅H₅, oxobenzoxazapineH-8), 7.10 (1H, d, J 8.5Hz, oxobenzoxazapineH-9), 7.09 (1H, m, oxobenzoxazapineH-6), 5.40 (1H,br s, 1H of C═CH₂), 5.32 (1H, br s, 1H of C═CH₂), 5.08 (1H, m,oxobenzoxazapineH-3), 4.76 (1H, dd, J 10.0, 6.0 Hz, 1H ofoxobenzoxazapineH-2), 4.33 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.18 (2H, s, CH ₂C₆H₅), 1.98 (3H, s, CCH₃); m/z:428 [M+H]⁺ (found [M+H]⁺, 428.1709, C₂₄H₂₁N₅O₃ requires [M+H]⁺428.1717).

(S)-5-benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.32-7.21 (7H, m, C₆H₅, oxobenzoxazapineH-6,H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.00 (1H, dd, J 10.5,6.5 Hz, oxobenzoxazapineH-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H ofoxobenzoxazapineH-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazapineH-2),4.15 (2H, s, CH₂C₆H₅); m/z: 444, 442 [M+H]⁺ (found [M+H]⁺, 444.0492,C₁₉H₁₆BrN₅O₃ requires [M+H]⁺ 444.0489).

(S,Z)-5-benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41-7.39 (2H, m,oxobenzoxazapineH-6, H-8), 7.29-7.22 (5H, m, C₆H₅), 7.15 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 6.31 (1H, s, CH═CC), 5.05 (1H, dt, J 11.5, 7.5Hz, oxobenzoxazapineH-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃), 1.57(6H, s, C(CH₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.9, 158.4,154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2,125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29.4; m/z: 480, 478[M+H—H₂O]⁺; m/z: 496, 494 [M−H]⁻ (found [M+H]⁺, 496.1743, C₂₅H₂₆ClN₅O₄requires [M+H]⁺ 496.1746).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28-7.20 (7H, m,oxobenzoxazapineH-6, H-8, C₆H₅), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.62 (2H, s, CCH₂N), 3.38(3H, s, NCH₃), 2.73-2.70 (4H, m, 4H of pyrrolidine), 1.86-1.82 (4H, m,4H of pyrrolidine); m/z: 485 [M+H]⁺ (found [M+H]⁺, 485.2322, C₂₇H₂₈N₆O₃requires [M+H]⁺ 485.2296).

(S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29-7.7.27 (2H,m, oxobenzoxazapineH-6, H-8), 7.25-7.18 (5H, m, C₆H₅), 7.10 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.0 Hz,oxobenzoxazapineH-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.78, 3.76 (4H, 2d ABsystem, J 4.5 Hz, 4H of morpholine), 3.50 (2H, s, CCH₂N), 3.39 (3H, s,NCH₃), 2.65, 2.63 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine); m/z:501 [M+H]⁺ (found [M+H]⁺, 501.2245, C₂₇H₂₈N₆O₄ requires [M+H]⁺501.2245).

Example 11

In this example, compounds of the disclosure were evaluated using abiochemical assay using the ADP-Glo™ technology.

ADP-Glo™ (Promega, Madison, Wis., USA) reagents were thawed at ambienttemperature. Kinase Detection Reagent was prepared by mixing kinasedetection buffer with the lyophilized kinase detection substrate.

A 500 ml stock volume of 5× Reaction Kinase Buffer was made by mixing1000 μl of 1M MgCl₂, 500 μl of 1M Tris-HCL pH7.4, 0.5 mg/ml (25 mg) ofBSA, and 3475 μl of distilled H₂O. A 3 ml 2× working stock volume ofReaction Kinase Buffer was made containing a final concentration of 100μM DTT and 4 mM MnCl₂.

Components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco,Calif., USA) were thawed on ice. Diluted RIPK1 was prepared in 1× KinaseReaction Buffer (diluted from 2× buffer) to 31 ng/well. A 166 M workingstock ATP assay solution was prepared in 1× Kinase Reaction Buffer(diluted from 2× buffer).

Compounds were serially diluted in DMSO from 250 uM in 4-fold dilutionsthen diluted 1:5 in 2× Reaction Buffer in a 96 well plate. 1.0 ul ofdiluted compound was added to a 384 well plate in duplicate. 2 μl ofdiluted Active RIPK1 was added to 384 well plate (do not add to column1)add 2× rxn buffer to column 1. AKT (Anaspec, Fremont, Calif., USA) at150 nM was combined with ATP working stock at equal volume and 2 ul/wellwere added to the 384 well plate. The final reaction volume was 5.0 μl.

The plate was quickly centrifuged and the reaction was incubated at 30°C. for 30 minutes. Adding 5 μl of ADP-Glo™ terminated the reaction. Theplate was quickly centrifuged and the reaction was incubated at roomtemperature for 40 minutes. Kinase Detection Reagent was then added andincubated at room temperature for 30 minutes. The relative light unit(RLU) of kinase reaction was determined by luminescent (Luminescence 0.1s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, Mass.,USA). IC₅₀ values obtained from this example are provided by Table 1.

TABLE 1 Compound RIPK1 ADP-Glo Kinase (IC₅₀) I-1 0.019 I-2 0.0157 I-30.0402 I-4 0.0568 I-5 0.0197 I-6 0.0724 I-7 0.021 I-8 0.0529 I-9 0.1892I-10 0.0429 I-11 0.0571 I-12 0.052 I-13 0.0539 I-14 0.073 I-15 0.1359I-16 1.633 I-17 0.4906 I-18 0.1645 I-19 0.1455 I-20 0.1528 I-21 0.077I-22 0.048 I-23 0.0352 I-24 0.0592 I-25 0.051 I-26 0.0656 I-27 0.1583I-28 0.0375 I-29 0.0124 I-30 0.0402 I-31 0.0334 I-32 0.0219 I-33 0.0145I-34 0.0492 I-35 0.0223 I-36 0.0338 I-37 0.0565 I-38 0.068 I-39 0.0364I-40 0.0887 I-41 0.08 I-42 0.0477 I-43 0.0854 I-44 0.034 I-45 0.0825I-46 0.0437 I-47 0.0683 I-48 0.0624 I-49 0.0604 I-50 0.0234 I-51 0.0317I-52 0.0249 I-53 0.034 I-54 0.0269 I-55 0.0337 I-57 0.0215 I-58 0.011I-59 0.0579 I-60 0.0644 I-61 0.0654 I-62 0.0355 I-63 0.0303 I-64 0.019I-65 0.0639 I-66 0.0794 I-67 0.0415 I-68 0.0222 I-69 0.0286 I-70 1.155I-71 0.0217 I-73 0.0429 I-74 0.0518 I-75 0.0546 I-76 0.0449 I-77 0.0327I-78 0.0334 I-79 0.0347 I-80 0.0206 I-81 0.019 I-82 0.0255 I-83 0.0664I-84 0.0441 I-85 0.0423 I-86 0.6161 I-87 0.0187 I-88 0.0738 I-89 0.0527I-90 0.3649 I-91 0.3879 I-92 0.9325 I-93 0.0641 I-94 0.0333 I-95 0.0271I-96 0.0317 I-97 0.0858

Example 12

In this example, U937 and L929 cells were exposed to compounds of thepresent disclosure and a cell necroptosis assay was conducted toevaluate the compounds' activity against human RIP1 and murine RIP1.

U937 and L929 cells were obtained from the American Type CultureCollection (Manassa, Va., USA). Both cells were maintained inlogarithmic growth phase in complete RPMI 1640 media (Sigma, ST Louis,Mo., USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis,Mo., USA) at 37° C. with 5% CO₂. For necroptosis assay, L929 cells wereplated for 18 h in 100 μL/well medium at 10K cells/well in Costar96-well black clear-bottom plates (Fisher Scientific, Hampton, N.H.,USA); U937 cells were plated on the day of the assay in 50 μL/wellmedium containing 60 uM zVAD-fmk (Lonza, Basel, Switzerland) at 50Kcells/well. Medium from L929 cells were removed from the 96-well platesand replaced with 50 μL/well new medium containing 40 uM zVAD-fmk. Eachcompound of the present disclosure evaluated in this example wasserially diluted in DMSO from 2.5 mM in 4-fold dilutions, and thendiluted 1:125 in complete medium. 50 μL/well 2× of the compound was thenadded to the cells in the plates. The cells were pre-incubated with thecompound for 1 hour at 37° C. with 5% CO₂ and before addition of 10μL/well 11×TNFa (Peprotech, Rocky Hill, N.J., USA) to give a finalconcentration of 2 ng/mL for TNFa. The relative amount of necroptosiscells was determined by luminescent using a Wallac Victor2 Luminometer(PerkinElmer, Waltham, Mass., USA) and a CellTiter-Glo® Luminescent CellViability Reagent Assay (Promega, Madison, Wis., USA) added permanufacturer instructions after 18 hours of TNFa stimulation at 37° C.with 5% CO₂. Results from this example are summarized in Table 2. Thisexample establishes that embodiments of the compounds described hereinhave unexpectedly potent activity against human RIP1 and murine RIP1,which allows their assessment in in vivo mouse models of disease. Theseresults are useful in determining safe and effective doses for humans.

TABLE 2 L929-CTG- U937 Zvad TNF CTG recovery, L929, Recovery, U937,TNFa + zVAD TNFa + zVAD Compound (IC₅₀) (IC₅₀) I-1 2.356 0.0027 I-20.0319 I-3 0.4278 0.0049 I-4 0.0293 I-5 0.0188 0.0005 I-6 97.54 0.0438I-7 1.959 0.0009 I-8 0.0092 0.0014 I-9 0.3623 I-10 11.23 0.0079 I-1114.1 0.0081 I-12 41.95 0.0053 I-13 0.0138 I-14 5.878 0.0114 I-15 2.20.0048 I-16 5.669 0.0517 I-17 0.3683 0.0024 I-18 0.2797 0.0013 I-191.302 0.0027 I-20 53.37 0.0136 I-21 1.306 0.0025 I-22 3.383 0.0048 I-2314.5 0.0067 I-24 4.608 0.0036 I-25 0.4895 0.0027 I-26 0.6131 0.0044 I-270.0697 I-28 0.6735 0.0054 I-29 0.0088 0.0023 I-30 0.0723 0.0036 I-310.0337 I-32 17.74 0.0027 I-33 1.227 0.0015 I-34 9.592 0.0222 I-35 0.01780.0031 I-36 0.0014 0.0022 I-37 0.0002 0.001 I-38 0.0005 0.0036 I-390.0004 0.0027 I-40 0.0003 0.0023 I-41 0.0016 0.0052 I-42 0.0012 0.0033I-43 0.0009 0.0038 I-44 0.0002 0.0011 I-45 0.0003 0.0014 I-46 0.00040.0012 I-47 0.0015 0.0046 I-48 0.0005 0.0016 I-49 0.0012 0.005 I-500.0003 0.0011 I-51 0.0005 0.0017 I-52 0.0003 0.0009 I-53 0.0005 0.0018I-54 0.0003 0.0009 I-55 0.0006 0.002 I-57 0.0009 0.003 I-58 0.00020.0008 I-59 0.0007 0.0019 I-60 0.0024 0.0048 I-61 0.0013 0.0034 I-620.0007 0.002 I-63 0.0003 0.001 I-64 0.0001 0.0005 I-65 0.0415 0.042 I-660.0949 0.1886 I-67 0.0085 0.0152 I-68 0.0003 0.0007 I-69 0.0009 0.0022I-70 0.0195 0.1876 I-71 0.0002 0.0009 I-73 0.0027 0.0117 I-74 0.00020.0014 I-75 0.0014 0.0083 I-76 0.0024 0.0181 I-77 0.0003 0.0028 I-780.0009 0.0025 I-79 0.0008 0.0051 I-80 0.0007 0.0027 I-81 0.0012 0.0042I-82 0.0003 0.0019 I-83 0.0001 0.001 I-84 0.0122 0.0563 I-85 0.00060.0033 I-86 0.0006 0.0041 I-87 0.0292 0.1385 I-88 0.00009757 0.0007 I-890.0007 0.0045 I-90 0.0046 0.0091 I-91 0.0037 0.0198 I-92 0.4305 4.835I-93 0.9207 3.238 I-94 0.0046 0.022 I-95 0.0005 0.0014 I-96 0.00080.0031 I-97 0.0009 0.0017

Example 13

In this example, an acute hypothermia mouse model assay was used toevaluate the ability of compounds disclosed herein to inhibit TNF-alphainduced hypothermia.

Female C57BL/6 mice are randomly grouped and weighed on Day −1. On theday of the study (Day 0), mice are administered vehicle or test articleby oral gavage. Fifteen minutes after oral administration of testagents, each mouse is administered an intraperitoneal (IP) injection ofsolution containing recombinant human tumor necrosis factor alpha(TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature is measured at0 hours (before IP injections) and every hour via rectal probetemperature measuring device. Three (3) hours after IP injections ofTNF-a and zVAD/FMK, mice are euthanized by CO₂ asphyxiation and blood iscollected via cardiac puncture. Serum and plasma are harvested fordetermination of cytokine and compound levels, respectively. Separategroups of mice (satellite mice) are included for the determination ofcompound levels in plasma at the time of administration ofTNFa/zVAD-FMK.

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(WO 2014/125444), having a structure as illustrated below, was used as acomparative compound and was examined using a similar protocol asdescribed by WO 2014/125444. This comparative compound exhibited 93%inhibition at a dose of 30 mg/kg according to WO 2014/125444; however,in the inventors hands, the compound inhibited only 70% at 30 mg/kg. Incomparison, compound I-30 of the present disclosure achieved greaterthan 85% inhibition at a dose of just 5 mg/kg using the similar assayprotocol described above.

In view of the many possible embodiments to which the principles of thepresent disclosure may be applied, it should be recognized that theillustrated embodiments are only preferred examples and should not betaken as limiting. Rather, the scope of the present disclosure isdefined by the following claims. We therefore claim as our invention allthat comes within the scope and spirit of these claims.

We claim:
 1. A compound, having a formula

wherein R² is R^(a); R^(a) is independently for each occurrence H, D,C₁alkyl, substituted or non-substituted C₂₋₁₀aliphatic, substituted ornon-substituted C₁₋₁₀haloaliphatic, substituted or non-substitutedC₅₋₁₀aromatic, or substituted or non-substituted C₃₋₆heterocyclic;linker is CH₂ or R^(a), provided that R^(a) is not H or D; R⁶ is R^(b),—C(R^(f))₃, or —C(R^(f))═C(R^(f))₂; R^(b) is independently for eachoccurrence —OH, —SH, —OR^(c), —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃,—C(O)OH, —C(O)OR^(c), or —C(O)NR^(d)R^(d); R^(c) is independently foreach occurrence substituted or non-substituted C₁₋₁₀alkyl, substitutedor non-substituted C₂₋₁₀alkenyl, substituted or non-substitutedC₂₋₁₀alkynyl, or substituted or non-substituted C₃₋₆cycloalkyl; R^(d) isindependently for each occurrence H; substituted or non-substitutedC₁₋₆alkyl; substituted or non-substituted C₃₋₆cycloalkyl; substituted ornon-substituted C₃₋₆heterocyclic; substituted or non-substitutedC₅₋₁₀aryl; substituted or non-substituted C₅₋₁₀heteroaryl; or two R^(d)groups together with the nitrogen bound thereto provide a substituted ornon-substituted C₃₋₉heterocyclic group, or a substituted ornon-substituted C₅₋₁₀heteroaryl; R^(e) is independently for eachoccurrence halogen, substituted or non-substituted C₁₋₆alkyl,substituted or non-substituted C₂₋₁₀alkenyl, substituted ornon-substituted C₂₋₁₀alkynyl, substituted or non-substitutedC₁₋₆haloalkyl, substituted or non-substituted C₃₋₆cycloalkyl,substituted or non-substituted C₅₋₁₀heteroaryl, or —OR^(a); R^(f) isindependently for each occurrence R^(a), R^(b), or R^(e), or two R^(f)groups together with the carbon atom bound thereto provide a substitutedor non-substituted C₃₋₆cycloalkyl group or a substituted ornon-substituted C₃₋₁₀heterocyclic group; m is 1 to 4; and PG is an amineprotecting group.
 2. The compound of claim 1, wherein PG is a9-fluorenylmethoxycarbonyl group, a t-butyloxycarbonyl group, a tritylgroup, an allyloxycarbonyl group, or a benzyloxycarbonyl group.
 3. Thecompound of claim 1, wherein the linker is the linker is CH₂ or asubstituted or non-substituted C₂, C₃, or C₄ aliphatic group.
 4. Thecompound of claim 3, wherein the substituted or non-substituted C₂aliphatic group comprises a substituted or non-substituted alkyne andwherein R⁶ is —C(R^(f))₃, wherein one R^(f) is R^(e) and each otherR^(f) independently for each occurrence is substituted ornon-substituted C₁₋₄alkyl.
 5. The compound of claim 4, wherein R^(e) is—OR^(a), wherein R^(a) is H.
 6. The compound of claim 4, wherein thesubstituted or non-substituted C₁₋₄alkyl is methyl.
 7. The compound ofclaim 1, wherein the linker is a substituted or non-substituted alkyneand wherein R⁶ is —C(R^(f))₃, wherein one R^(f) is OR^(a) wherein R^(a)is H, and the remaining two R^(f) groups together with the carbon atombound thereto provide an oxetane.
 8. The compound of claim 1, whereinthe linker is a substituted or non-substituted alkyne and wherein R⁶ is—C(R^(f))₃, wherein one R^(f) is OR^(a) wherein R^(a) is H, and theremaining two R^(f) groups together with the carbon atom bound theretoprovide a tetrahydropyran.
 9. The compound of claim 1, wherein thelinker-R⁶ group is selected from


10. The compound of claim 1, wherein the compound is


11. A compound, having a formula

wherein linker is CH₂ or R^(a), provided that R^(a) is not H or D; R⁶ isR^(b), wherein R^(b) is selected from —OH, —C(O)OH, —C(O)OR^(c), or—C(O)NR^(d)R^(d); ring B is substituted or non-substituted 5-membered or6-membered heteroaryl; L is a heteroatom, CH₂, or R^(a), provided thatR^(a) is not H or D; Z is substituted or non-substituted C₁₋₁₀aliphaticor

R² and R³ independently are R^(a); R⁴ and R⁵ independently are R^(e);R^(a) is independently for each occurrence H, D, C₁alkyl, substituted ornon-substituted C₂₋₁₀aliphatic, substituted or non-substitutedC₁₋₁₀haloaliphatic, substituted or non-substituted C₅₋₁₀aromatic, orsubstituted or non-substituted C₃₋₆heterocyclic; R^(b) is independentlyfor each occurrence —OH, —SH, —OR^(c), —SR^(c), —NR^(d)R^(d),—Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(d)R^(d); R^(c) isindependently for each occurrence substituted or non-substitutedC₁₋₁₀alkyl, substituted or non-substituted C₂₋₁₀alkenyl, substituted ornon-substituted C₂₋₁₀alkynyl, or substituted or non-substitutedC₃₋₆cycloalkyl; R^(d) is independently for each occurrence H;substituted or non-substituted C₁₋₆alkyl; substituted or non-substitutedC₃₋₆cycloalkyl; substituted or non-substituted C₃₋₆heterocyclic;substituted or non-substituted C₅₋₁₀aryl; substituted or non-substitutedC₅₋₁₀heteroaryl; or two R^(d) groups together with the nitrogen boundthereto provide a substituted or non-substituted C₃₋₉heterocyclic group,or a substituted or non-substituted C₅₋₁₀heteroaryl; R^(e) isindependently for each occurrence halogen, substituted ornon-substituted C₁₋₆alkyl, substituted or non-substituted C₂₋₁₀alkenyl,substituted or non-substituted C₂₋₁₀alkynyl, substituted ornon-substituted C₁₋₆haloalkyl, substituted or non-substitutedC₃₋₆cycloalkyl, substituted or non-substituted C₅₋₁₀heteroaryl, or—OR^(a); R^(f) is independently for each occurrence R^(a), R^(b), orR^(e), or two R^(f) groups together with the carbon atom bound theretoprovide a substituted or non-substituted C₃₋₆cycloalkyl group or asubstituted or non-substituted C₃₋₁₀heterocyclic group; m is 1 to 4; nis 0, 1 or 2; and p is 0, 1, 2, 3, 4, or
 5. 12. The compound of claim11, wherein the linker is a substituted or non-substituted C₂, C₃, or C₄aliphatic group.
 13. The compound of claim 11, wherein R⁶ is R^(b),wherein R^(b) is OH, —C(O)OH, —C(O)OEt, or —C(O)NH₂.
 14. The compound ofclaim 11, wherein the linker-R⁶ group is selected from


15. The compound of claim 11, wherein the compound is selected from


16. A compound, having a formula

or a salt thereof, wherein: R² is R^(a); R^(a) is independently for eachoccurrence H, D, C₁alkyl, substituted or non-substituted C₂₋₁₀aliphatic,substituted or non-substituted C₁₋₁₀haloaliphatic, substituted ornon-substituted C₅₋₁₀aromatic, or substituted or non-substitutedC₃₋₆heterocyclic; linker is CH₂ or R^(a), provided that R^(a) is not Hor D; R⁶ is R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂; R^(b) isindependently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(d)R^(d);R^(c) is independently for each occurrence substituted ornon-substituted C₁₋₁₀alkyl, substituted or non-substituted C₂₋₁₀alkenyl,substituted or non-substituted C₂₋₁₀alkynyl, or substituted ornon-substituted C₃₋₆cycloalkyl; R^(d) is independently for eachoccurrence H; substituted or non-substituted C₁₋₆alkyl; substituted ornon-substituted C₃₋₆cycloalkyl; substituted or non-substitutedC₃₋₆heterocyclic; substituted or non-substituted C₅₋₁₀aryl; substitutedor non-substituted C₅₋₁₀heteroaryl; or two R^(d) groups together withthe nitrogen bound thereto provide a substituted or non-substitutedC₃₋₉heterocyclic group, or a substituted or non-substitutedC₅₋₁₀heteroaryl; R^(e) is independently for each occurrence halogen,substituted or non-substituted C₁₋₆alkyl, substituted or non-substitutedC₂₋₁₀alkenyl, substituted or non-substituted C₂₋₁₀alkynyl, substitutedor non-substituted C₁₋₆haloalkyl, substituted or non-substitutedC₃₋₆cycloalkyl, substituted or non-substituted C₅₋₁₀heteroaryl, or—OR^(a); R^(f) is independently for each occurrence R^(a), R^(b), orR^(e), or two R^(f) groups together with the carbon atom bound theretoprovide a substituted or non-substituted C₃₋₆cycloalkyl group or asubstituted or non-substituted C₃₋₁₀heterocyclic group; and m is 1 to 4.17. The compound of claim 16, wherein the linker is the linker is CH₂,or a substituted or non-substituted C₂, C₃, or C₄ aliphatic group. 18.The compound of claim 17, wherein the substituted or non-substituted C₂aliphatic group comprises a substituted or non-substituted alkyne andwherein R⁶ is —C(R^(f))₃, wherein one R^(f) is R^(e) and each otherR^(f) independently for each occurrence is C₁₋₄alkyl.
 19. The compoundof claim 18, wherein R^(e) is —OR^(a), wherein R^(a) is H.
 20. Thecompound of claim 18, wherein the substituted or non-substitutedC₁₋₄alkyl is methyl.
 21. The compound of claim 16, wherein the linker-R⁶group is selected from


22. The compound of claim 16, wherein the compound is selected from

or an HCl salt thereof.